EP0237962A2 - 2-Azolylmethyl-2-aryl-1,3-dioxolanes and their preparation, compositions containing them and their use - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which A is CH or N, Ar is phenyl, naphthyl or thienyl, R 1 is alkyl or halogen and Y is a number of nitrogen-containing heterocycles have excellent antifungal activity. Compounds III a <IMAGE> are valuable intermediates for their preparation.

Description

The invention relates to heterocyclic substituted 2-azolylmethyl-2-aryl-4 - [(4-piperazino-phenoxy) -methyl] -1,3-dioxolanes including their salts, processes for their preparation, medicaments containing these compounds and their use in particular as an antifungal.

Antifungal or fungicidally active 2-azolylmethyl-2-aryl-4 - [(4-piperazino-phenoxy) -methyl] -1,3-dioxolanes are already known and are u.a. in DE-OS 2 804 096, and EP-OS 7696. The best known representatives from the large number of the compounds described are 2-S, (R) - (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-R, (S) - [4- (4 -acetyl-piperazin-1-yl) phenoxymethyl] -1,3-dioxolane (ketoconazole) and 2-S, (R) - (2,4-dichlorophenyl) -2- (1,2,4-triazol-1 -ylmethyl) -4-R, (S) - [4- (4-isopropyl-piperazin-1-yl) -phenoxymethyll-1,3-dioxolane (terconazole), which are commercially available as antifungals (see DOS 2 804 096, Example 20 and Example 53), ketoconazole being used primarily as a systemically active and terconazole as a topically active antifungal. However, the antifungal activity and in particular the tolerance of the known compounds are not always entirely satisfactory.

in der

• A CH oder N,
• Ar Naphthyl, Thienyl, Halothienyl oder eine unsubstituierte oder eine bis zu 3 Substituenten tragende Phenylgruppe bedeutet, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, J, CF₃, OCH₃, OC₂H₅, CH₃, C₂H₅ oder Phenoxy bedeuten,
• R C₁-C₃-Alkyl, F oder Cl,
• g 0, 1 oder 2 und
• Y die folgenden heterocyclischen Reste
  
  in denen
• R² H, C₁-C₈-Alkyl, C₁-C_4-Alkoxy, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, J, CF₃, O^CH ₃, OC₂H₅, NO₂ oder C₁-C₄-Alkyl bedeuten, oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl-C₁-C₂-alkylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OC₂H₅, ^CH₃ oder C₂H₅ bedeuten, oder beim Rest a₁ zusätzlich C₁-C₄-Alkylthio, eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Benzylthiogruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten, bedeutet und
• R³ H, OH, Cl, C₁-C₄-Alkoxy oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Benzyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅, ^CH ₃ oder C₂H₅ bedeuten, und beim heterocyclischen Rest a₁ zusätzlich C₁-C₄-Alkyl oder eine unsubstituierte oder mit einem F, Cl, Br, OCH₃, OC₂H₅, ^CH ₃ oder C₂H₅ substituierte Phenylgruppe und beim heterocyclischen Rest b₁ zusätzlich C₁-C₄-Alkyl oder eine unsubstituierte oder eine 1 oder 2 Substituenten tragende Phenyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten,
• R⁴ H, Cl, Br, C₁-C₄-Alkyl oder CN,
• R⁵ H, C₁-C₄-Alkyl, Prop-2-en-1-yl, Prop-2-in-1-yl oder Benzyl,
• p 0 oder 1 bedeutet, wobei in a₁, a₂ und c der Phenylenrest über die 2,3 oder 4-Position gebunden ist, und
• R⁶ H, C₁-C₈-Alkyl, (C₃-C₆-Cycloalkyl)-C₁-C₃-alkyl, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, J, OCH₃, OC₂H₅, 1,2--O-CH₂-O-, CF₃ oder C₁-C₄-Alkyl bedeuten, eine unsubstituierte oder im Phenylrest durch OCH₃, OC₂H₅, 1,2--O-CH₂-O-, CF₃, ^F, Cl oder C₁-C₄-Alkyl substituierte Phenyl-C₁-C₂- alkylgruppe, oder CF₃, und
• R⁷ und R⁸ unabhängig voneinander H, C₁-C₈-Alkyl, C₁-C₄-Alkoxy oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl-oder Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃ oder OC₂H₅ bedeuten, und wobei R⁷ darüberhinaus auch OH bedeuten kann, und
• R⁹ H, Cl,Br oder CN bedeutet, oder
  
  
  oder
  
  in denen p 0 oder 1,
• _R ¹⁰ Cl, Br, OCH₃, OC₂H₅, CH₃ oder C₂H₅, n 0, 1 oder 2 bedeutet, wobei R¹⁰ in d₁ in 3,4,5 und/ oder 6-, in d₂ in 2,4,5 und/oder 6- und in d₃ in 2,3,5 und/oder 6-Stellung stehen kann, und
• _R ¹¹ Cl, OCH₃, CH₃ oder C₂H₅ bedeutet und in d₄ und d₅ in einer bzw. zwei der freien Positionen stehen kann, und der heterocyclische Rest d₄ über die 2, 3 oder 4-Stellung und der heterocyclische Rest d₅ über die 5,6,7 oder 8-Stellung und die Phenyleneinheit im Rest d₁ über die 2,3 oder 4-(para)-Stellung gebunden ist, bedeutet,

sowie deren physiologisch verträgliche Säureadditionssalze wertvolle antimykotische bzw. fungizide Eigenschaften besitzen. Sie sind daher zur Bekämpfung von Mykosen bei Mensch und Tier sowie zur Bekämpfung von Pilzbefall bei Pflanzen und auf Werkstoffen geeignet.It has now been found that 2-azolylmethyl-2-aryl-4 - [(4-piperazino-phenoxy) -methyl] -1,3-dioxolanes of the formula

in the

• A CH or N,
• Ar denotes naphthyl, thienyl, halothienyl or an unsubstituted or a phenyl group which has up to 3 substituents, where the substituents can be identical or different and F, Cl, Br, J, CF ₃ , OCH ₃ , OC ₂ H ₅ , CH ₃ , C ₂ H ₅ or phenoxy,
• RC ₁ -C ₃ alkyl, F or Cl,
• g 0, 1 or 2 and
• Y the following heterocyclic radicals
  
  in which
• R ² H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be identical or different and F, Cl, Br, J, CF ₃ , O ^CH ₃ , OC ₂ H ₅ , NO ₂ or C ₁ -C ₄ alkyl, or an unsubstituted or a phenyl C ₁ -C ₂ alkyl group carrying 1 or 2 substituents in the phenyl radical, the substituents being identical to or may be different and mean F, Cl, Br, OC ₂ H ₅ , ^C H ₃ or C ₂ H ₅ , or in the case of the a ₁ radical additionally C ₁ -C ₄ -alkylthio, one unsubstituted or one having 1 or 2 substituents in the phenyl radical Benzylthio group, where the substituents can be identical or different and mean F, Cl, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , and
• R ³ H, OH, Cl, C ₁ -C ₄ alkoxy or an unsubstituted or a benzyloxy group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , ^CH ₃ or C ₂ H ₅ , and in the heterocyclic radical a ₁ additionally C ₁ -C ₄ alkyl or an unsubstituted or with an F, Cl, Br, OCH ₃ , OC ₂ H ₅ , ^CH ₃ or C ₂ H ₅ substituted phenyl group and in the heterocyclic radical b ₁ additionally C ₁ -C ₄ alkyl or an unsubstituted or 1 or 2 substituent-bearing phenyloxy group, where the substituents can be the same or different and F, Cl, Br, OCH ₃ , OC ₂ Is H ₅ , CH ₃ or C ₂ H ₅ ,
• R ⁴ H, Cl, Br, C ₁ -C ₄ alkyl or CN,
• R ⁵ H, C ₁ -C ₄ -alkyl, prop-2-en-1-yl, prop-2-in-1-yl or benzyl,
• p denotes 0 or 1, the phenylene radical being bonded via the 2,3 or 4 position in a ₁ , a ₂ and c, and
• R ⁶ H, C ₁ -C ₈ alkyl, (C ₃ -C ₆ cycloalkyl) -C ₁ -C ₃ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be identical or different and F , Cl, Br, J, OCH ₃ , OC ₂ H ₅ , 1,2 - O-CH ₂ -O-, CF ₃ or C ₁ -C ₄ alkyl, an unsubstituted or in the phenyl radical by OCH ₃ , OC ₂ H ₅ , 1,2 - O-CH ₂ -O-, CF ₃ , ^F, Cl or C ₁ -C ₄ alkyl-substituted phenyl-C ₁ -C ₂ -alkyl group, or CF ₃ , and
• R ⁷ and R ⁸ independently of one another are H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or an unsubstituted or a phenyl or benzyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ or OC ₂ H ₅ , and where R ^{7 can} also mean OH, and
• R ⁹ denotes H, Cl, Br or CN, or
  
  
  or
  
  where p is 0 or 1,
• _R ^{10 is} Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , n is 0, 1 or 2, where R ¹⁰ in d ₁ in 3,4,5 and / or 6-, in d ₂ in 2,4,5 and / or 6- and in d ₃ in 2,3,5 and / or 6-position, and
• _R ¹¹ denotes Cl, OCH ₃ , CH ₃ or C ₂ H ₅ and can be in one or two of the free positions in d ₄ and d ₅ , and the heterocyclic radical d ₄ via the 2, 3 or 4 position and the heterocyclic radical d _{5 is} bonded via the 5,6,7 or 8 position and the phenylene unit in the radical d ₁ is bonded via the 2,3 or 4- (para) position,

and their physiologically compatible acid addition salts have valuable antifungal or fungicidal properties. They are therefore suitable for combating mycoses in humans and animals and for combating fungal attack in plants and on materials.

In this context, the term "halothienyl" means a thienyl radical linked in the 2- or 3-position, which can be substituted in any position with an F, Cl, Br or J atom, preferably Br or Cl, below the expressions "C ₁ -C ₃ -, ^C ₁ - ^C ₄ - and C ₁ -C ₈ -alkyl" an unbranched or branched hydrocarbon radical having 1-3, 1-4 or 1-8 C atoms, under the expression " C ₃ -C ₆ or C ₅ -C ₆ cycloalkyl "is a cyclopropyl, butyl, pentyl or cyclohexyl or cyclopentyl or cyclohexyl radical, under the expression" C ₁ -C ₄ -A ^lk ox ^y "or" C ₁ -C ₄ alkylthio "to understand an alkoxy or alkylthio group whose hydrocarbon radical has the meaning given under the expression" C ₁ -C ₄ alkyl ".

• A CH oder N,
• Ar eine durch 1 oder 2 F- oder Cl-Atome substituierte Phenylgruppe,
• _R ¹ CH₃ oder C₂H₅
• g 0 oder 2
• Y
• zu den heterocyclischen Resten a₁, a₂, b₁, b₂ und c:
• R² H, C₁-C₄-Alkyl, CH₃0 oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl- oder eine Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br oder OCH₃ bedeuten,
• R³ H oder C₁-C₄-Alkoxy und beim heterocyclischen Rest _a1 zusätzlich C_H3 oder eine unsubstituierte oder eine mit einem F, Cl, OCH₃ oder CH₃ substituierte Phenylgruppe und beim Rest b₁ zusätzlich eine unsubstituierte oder eine 1 oder 2 Substituenten tragende Phenyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃ oder bedeuten, OC₂H₅ bedeuten,
• R⁴ H oder CN und beim heteroxyclischen Rest a₁ zusätzlich C₁-C₄-Alkyl,
• R⁵ CH₃
• p 0 oder 1
• R⁶ H, C₁-C₈-Alkyl, (C₅-C₆-Cycloalkyl)-C₁-C₂-alkyl, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, ^OC ₂ ^H ₅ oder CF₃ bedeuten, eine unsubstituierte oder im Phenylrest durch OCH₃, CF₃, F oder Cl substituierte Benzylgruppe oder CF₃,
• _R ⁷, R⁸ unabhängig voneinander C₁-C₈-Alkyl, C₁-C₄-Alkoxy, eine unsubstituierte oder eine im Phenylrest durch F, Cl, OCH₃ oder OC₂H₅ substituierte Phenyl- oder Benzylgruppe und R⁷ darüber hinaus auch H oder OH
• _R ⁹ H oder CN
  zu den heterocyclischen Resten d₁, d₂, d₃, d₄, d₅, d₆ und d₇:
  • p 0 oder 1,
• R¹⁰ Cl, CH₃ oder C₂H₅,
• n 0 oder 1, wobei R¹⁰ in d₃ bevorzugt in 2-Stellung steht, und
• R¹¹ Cl, wobei die Phenyleneinheit im Rest d₁ bevorzugt über die 4-Stellung gebunden ist.

Preferred compounds of the formula I are those in which at least one of the substituents or indices has the following meaning:

• A CH or N,
• Ar is a phenyl group substituted by 1 or 2 F or Cl atoms,
• _R ¹ CH ₃ or C ₂ H ₅
• g 0 or 2
• Y
• to the heterocyclic radicals a ₁ , a ₂ , b ₁ , b ₂ and c:
• R ² H, C ₁ -C ₄ alkyl, CH ₃ 0 or an unsubstituted or a phenyl radical carrying 1 or 2 substituents or a benzyl group, the substituent ducks can be the same or different and represent F, Cl, Br or OCH ₃ ,
• R ³ H or C ₁ -C ₄ alkoxy and, in the case of the heterocyclic radical _a1, additionally C _H3 or an unsubstituted or a phenyl group substituted by an F, Cl, OCH ₃ or CH _3, and additionally an unsubstituted or a 1 or 2 by the radical b ₁ Phenyloxy group carrying substituents, where the substituents can be identical or different and mean F, Cl, Br, OCH ₃ or OC ₂ H ₅ ,
• R ^{4 is} H or CN and, in the case of the heteroxyclic radical a _1, additionally C ₁ -C ₄ -alkyl,
• R ⁵ CH ₃
• p 0 or 1
• R ⁶ H, C ₁ -C ₈ alkyl, (C ₅ -C ₆ cycloalkyl) -C ₁ -C ₂ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F , Cl, Br, OCH ₃ , ^OC ₂ ^H ₅ or CF ₃ , an unsubstituted or substituted in the phenyl radical by OCH ₃ , CF ₃ , F or Cl or CF ₃ ,
• _R ⁷ , R ⁸ independently of one another are C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or a phenyl or phenyl group substituted by F, Cl, OCH ₃ or OC ₂ H ₅ and R ⁷ above also H or OH
• _R ⁹ H or CN
  for the heterocyclic radicals d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and d ₇ :
  • p 0 or 1,
• R ¹⁰ Cl, CH ₃ or C ₂ H ₅ ,
• n is 0 or 1, where R ¹⁰ in d _{3 is} preferably in the 2 position, and
• R ¹¹ Cl, the phenylene unit in the rest d ₁ preferably being bonded via the 4-position.

• A CH oder N
• Ar 2.4-Dichlorphenyl
• R¹ C^H ₃
• g 0 oder 2
• Y zu den heterocyclischen Resten a₁, a2, b₁, b₂ und c:
• R² CH₃ oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl- oder eine Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F oder Cl und in der Phenylgruppe und beim Rest a₁ bei der Phenyl- und der Benzylgruppe zusätzlich OCH₃ bedeuten, und beim Rest a₁ zusätzlich C₂-C₄-Alkyl,
• R³ beim Rest a₁, falls p=0 ist, CH₃ oder eine unsubstituierte oder durch ein F, Cl oder OCH₃ substituierte Phenylgruppe, und falls p=1 ist, H, beim Rest b₁ H oder eine unsubstituierte oder durch F, Cl, OCH₃ oder OC₂H₅ substituierte Phenyloxygruppe,
• R⁴ H oder beim Rest a₁, falls p=0 ist, zusätzlich CH₃
• _R ⁵ C^H ₃
• p bei den heterocyclischen Resten a₁ und a₂ 0 oder 1 und bei dem heterocyclischen Rest C 1
• R⁶ H, CH₃ oder eine unsubstituierte oder durch F, Cl, OCH₃ oder OC₂H₅ einfach substituierte Phenylgruppe,
• R⁷, R⁸ unabhängig voneinander CH₃ oder eine unsubstituierte oder eine durch F, Cl oder OCH₃ substituierte Phenylgruppe und R⁷ darüber hinaus auch H oder C₁-C₄-Alkoxy,
• R9 H zu den heterocyclischen Resten d₁, d₂, d_3' d₄, d₅, d₆ und d₇:
  • p 0 oder 1
  • n 0,
  
  wobei der Rest d₄ bevorzugt über die 2-Stellung und der Rest d₅ bevorzugt über die 6- oder 7-Stellung gebunden ist.

Compounds of the formula I in which at least one of the substituents or indices has the following meaning are particularly preferred:

• A CH or N
• Ar 2.4 dichlorophenyl
• R ¹ C ^H ₃
• g 0 or 2
• Y to the heterocyclic radicals a ₁ , a2, b ₁ , b ₂ and c:
• R ² CH ₃ or an unsubstituted or a phenyl radical carrying 1 or 2 substituents or a benzyl group, where the substituents can be the same or different and F or Cl and in the phenyl group and the rest a ₁ in the phenyl and benzyl group additionally mean OCH ₃ , and in the remainder a ₁ additionally C ₂ -C ₄ alkyl,
• R ³ in the a ₁ radical, if p = 0, CH ₃ or an unsubstituted or substituted by an F, Cl or OCH ₃ phenyl group, and if p = 1, H, in the b ₁ radical H or an unsubstituted or by F , Cl, OCH ₃ or OC ₂ H ₅ substituted phenyloxy group,
• R ⁴ H or in the case of the rest a ₁ , if p = 0, additionally CH ₃
• _R ⁵ C ^H ₃
• p for the heterocyclic radicals a ₁ and a ₂ 0 or 1 and for the heterocyclic radical C 1
• R ⁶ H, CH ₃ or an unsubstituted or simply substituted by F, Cl, OCH ₃ or OC ₂ H ₅ ,
• R ⁷ , R ⁸ independently of one another are CH ₃ or an unsubstituted or a phenyl group which is substituted by F, Cl or OCH ₃ and R ⁷ moreover also H or C ₁ -C ₄ alkoxy,
• R9 H for the heterocyclic radicals d ₁ , d ₂ , d _{3 '} d ₄ , d ₅ , d ₆ and d ₇ :
  • p 0 or 1
  • n 0,
  
  where the residue d _{4 is} preferably bonded via the 2-position and the residue d ₅ preferably via the 6- or 7-position.

Compounds in which Y is d ₆ or d ₇ are not particularly preferred.

The invention further relates to the possible stereoisomers of the formula I, both as diastereomer racemates and as pure enantiomers, and their pharmaceutically acceptable salts. This applies in particular to the stereoisomers possible because of the 2,4-disubstitution of the 1,3-dioxolane ring; the 2-azolylmethyl group can be arranged in the cis or trans position relative to the 4-position substituent, the substituted phenoxymethyl group. The cis isomers are among the preferred compounds according to the invention.

Salts of the compounds of the formula I according to the invention are those with physiologically acceptable inorganic and organic acids, such as, for example, chlorine, bromine or hydrogen iodide, sulfur, phosphorus, saltpetre, benzene sulfone, toluenesulfone, sulfamine, methyl sulfur , Vinegar, propion, oil, palmitin, stearin, malon, malein, amber, glutar, apple, wine, lemon, fumar, milk, glycol, pyruvate, benzoin , Toluic, glutamic, furancarboxylic, salicylic or mandelic acid into consideration. Salts with physiologically compatible inorganic acids, strongly to moderately acidic derivatives of such acids or with fumaric acid are preferred.

The compounds of the invention differ significantly from the known azolylmethyl-2-aryl-4-f (4-piperazino-phenoxy) -methyl] -1,3-dioxolanes, which are active against fungi and bacteria, by the nature of the substituents on the Piperazinophenoxymethyl unit in the 4-position of the dioxolane ring as well as through the optional additional substitution of the phenyl ring of the 4-position phenoxy group.

Surprisingly, the 2-azolyl-2-aryl-4 - [(4-piperazino-phenoxy) methyl] -1,3-dioxolanes according to the invention have a broader and better antifungal activity than the known 2-azolylmethyl-2-aryl-1, 3-dioxolane derivatives and as the well-known 2-S, (R) - (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-R, (S) - [4- (4-acetylpiperazine -1-yl) phenoxymethyl] -1,3-dioxolane (ketoconazole).

• A) eine Verbindung der Formel II
  
  in der
  • A und Ar die zu Formel I angegebenen Bedeutungen haben und
  • E Halogen wie F, Cl, Br, J oder Acyloxy, wie Acetoxy, Trifluoracetyloxy, Benzoyloxy, Nitrobenzoyloxy, _C1-C₃-Alkylsulfonyloxy, wie Methansulfonyloxy, oder Arylsulfonyloxy, wie Benzol-, Nitrobenzol-, Brombenzol- oder Toluolsulfonyloxy, bedeutet,
  
  mit einer Verbindung der Formel III
  
  in der
  • M H, ein Alkali- oder Erdalkalimetall, insbesondere Li, ^Na oder K, oder NH₄ bedeutet und
  • R¹, g und Y die zu Formel I angegebenen Bedeutungen haben, umsetzt, oder daß man
• B) eine Verbindung der Formel IV,
  
  in der
  • Ar die zu Formel I und E und E' die zu Formel II für E angegebenen Bedeutungen haben,
    zunächst mit einer Verbindung der Formel III umsetzt und hierbei eine Verbindung der Formel V herstellt,
    
  in der
  • Ar, R¹, g und Y die zu Formel I und E' die zu Formel II für E angegebenen Bedeutungen haben,
    und anschließend eine Verbindung der Formel V mit einer Verbindung der Formel VI umsetzt,
    
    in der A, CH oder N und
    • M' H, ein Alkali- oder Erdalkalimetall oder Si(CH₃)₃ bedeutet,
    
    oder daß man
• C) eine Verbindung der Formel VII,
  
  in der A und Ar die zu Formel I angegebenen Bedeutungen haben, mit einem 1,2-Diol der Formel VIII
  
  in der R¹, g und Y die zu Formel I angegebenen Bedeutungen haben, umsetzt,
  oder daß man
• D) eine Verbindung der Formel IX,
  
  in der A, Ar, R¹ und g die zu Formel I angegebenen Bedeutungen haben, mit einer Verbindung der Formel X,
  
  in der E" Cl, Br, J, Acyloxy, wie Acetyloxy oder Benzoyloxy, Alkylsulfonyloxy, wie Methansulfonyloxy, oder Arylsulfonyloxy, wie Benzol-, Nitrobenzol- oder Toluolsulfonyloxy, bedeutet und Y die zu Formel I unter a₁, a₂, b₁, b₂, c, d₁, d₂, d₃, d₄, d₅, d₆ und d₇ angegebenen Bedeutungen hat, umsetzt, und gegebenenfalls die nach Weg A)-D) erhaltenen Verbindungen der Formel I mit anorganischen oder organischen Säuren in ihre physiologisch verträglichen Säureadditionssalze überführt.

The invention further relates to a process for the preparation of the compounds of formula I and their salts, which is characterized in that

• A) a compound of formula II
  
  in the
  • A and Ar have the meanings given for formula I and
  • E halogen such as F, Cl, Br, J or acyloxy, such as acetoxy, trifluoroacetyloxy, benzoyloxy, nitrobenzoyloxy, _C1 -C ₃ alkylsulfonyloxy, such as methanesulfonyloxy, or arylsulfonyloxy, such as benzene, nitrobenzene, bromobenzene or toluenesulfonyloxy
  
  with a compound of formula III
  
  in the
  • MH, an alkali or alkaline earth metal, in particular Li, ^N a or K, or NH ₄ means and
  • R ¹ , g and Y have the meanings given for formula I, or that
• B) a compound of the formula IV,
  
  in the
  • Ar have the meanings given for formula I and E and E 'for E in formula II,
    first reacted with a compound of the formula III and in doing so produces a compound of the formula V
    
  in the
  • Ar, R ¹ , g and Y have the meanings given for formula I and E 'for E in formula II,
    and then a compound of formula V with a Reacting compound of formula VI,
    
    in the A, CH or N and
    • M 'denotes H, an alkali or alkaline earth metal or Si (CH ₃ ) ₃ ,
    
    or that one
• C) a compound of formula VII,
  
  in which A and Ar have the meanings given for formula I, with a 1,2-diol of the formula VIII
  
  in which R ¹ , g and Y have the meanings given for formula I,
  or that one
• D) a compound of formula IX,
  
  in which A, Ar, R ¹ and g have the meanings given for formula I, with a compound of formula X,
  
  in which E "denotes Cl, Br, J, acyloxy, such as acetyloxy or benzoyloxy, alkylsulfonyloxy, such as methanesulfonyloxy, or arylsulfonyloxy, such as benzene, nitrobenzene or toluenesulfonyloxy, and Y represents the formula I under a ₁ , a ₂ , b ₁ , b ₂ , c, d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and d ₇ has the meanings indicated, and, if appropriate, the compounds of the formula I obtained according to route A) -D) with inorganic or converted organic acids into their physiologically compatible acid addition salts.

In this context, the term "acyloxy" is understood to mean a straight-chain or branched C ₁ -C 4 -alkanoyloxy radical or a benzoyloxy radical which is unsubstituted in the phenyl nucleus or substituted with up to 2 identical or different substituents, the substituents CH ₃ , OCH ₃ , F, Cl, or Br can mean, and under the expression

"Arylsulfonyloxy" is an unsubstituted or a phenylsulfonyloxy or a naphthylsulfonyloxy radical which is substituted by a ^C 1, Br, CH ₃ , C ₂ ^H ₅ , OCH ₃ , OC ₂ H ₅ or NO ₂ and is understood by the expression "C ₁ - C ₃ -Alkylsulfonyloxy "to understand an n-alkanesulfonic acid residue with 1-3 C atoms.

• a) eine Verbindung der Formel Xa₁ oder der Formel Xa₂
  
  in denen R²-R⁵ die zu Formel I angegebenen Bedeutungen haben und E", Cl bedeutet, oder
• b) eine Verbindung der Formel Xb₁ oder der Formel Xb₂
  
  in denen R², R³, R5 und _R ⁶ die zu Formel I angegebenen Bedeutungen haben und E" Br bedeutet, oder
• c) eine Verbindung der Formel Xc,
  
  in der R⁷, R⁸, R⁹ und p die zu Formel I angegebenen Bedeutungen haben und E" Cl oder Br bedeutet, oder
• d) eine Verbindung der Formel Xd₁ der Formel Xd₂, der Formel Xd₃, der Formel Xd₄, der Formel Xd₅, der Formel Xd₆ oder der Formel Xd₇,
  
  
  
  in denen R¹⁰, R¹¹, p und n die zu Formel I angegebenen Bedeutungen haben und E" Cl oder Br bedeutet.

For reaction with a compound of formula IX either are preferably used

• a) a compound of the formula Xa ₁ or of the formula Xa ₂
  
  in which R ² -R ^{5 have} the meanings given for formula I and E ", Cl, or
• b) a compound of the formula Xb ₁ or of the formula Xb ₂
  
  in which R ² , R ³ , R5 and _R ^{6 have} the meanings given for formula I and E "Br", or
• c) a compound of the formula Xc,
  
  in which R ⁷ , R ⁸ , R ⁹ and p have the meanings given for formula I and E "is Cl or Br, or
• d) a compound of the formula Xd _{1 of} the formula Xd ₂ , the formula Xd ₃ , the formula Xd ₄ , the formula Xd ₅ , the formula Xd ₆ or the formula Xd ₇ ,
  
  
  
  in which R ¹⁰ , R ¹¹ , p and n have the meanings given for formula I and E "is Cl or Br.

Process variant A), where in the compounds of the formula II E preferably denotes Cl, Br, acetoxy, trifluoroacetoxy, methanesulfonyloxy or (subst.) Phenylsulfonyloxy, is used at a temperature between 20 ° C. and 160 ° C., advantageously between 40 ° C and 120 ° C, in the presence of a base and advantageously in an inert organic solvent, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone-2, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, 4-methyl-2-pentanone, methanol, ethanol, isopropyl alcohol, propanol, butanol, pentanol, tert-butyl alcohol, methyl glycol, methylene chloride, acetonitrile or an aromatic hydrocarbon such as benzene, chlorobenzene, toluene or xylene. Mixtures of the solvents mentioned by way of example can also be used.

Suitable bases are, for example, alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, amides, alcoholates or hydrides such as e.g. Sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, amide or methylate, potassium t-butoxide or sodium hydride, or organic bases, e.g. tertiary amines such as triethylamine, tributylamine, ethylmorpholine or pyridine, dimethylaminopyridine, quinoline or 1,5-diazabicyclo- [5,4,01undec-5-ene (DBU).

The reaction can also be carried out under the conditions of a phase transfer reaction by reacting the reactants in a suitable solvent such as ether, dioxane, tetrahydrofuran, methylene chloride, N, N-dimethylform- or acetamide, N-methylpyrrolidone- (2), butanol , tert-butanol, an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene, toluene or xylene, methyl glycol, anisole or chlorobenzene with vigorous stirring in the presence of a phase transfer catalyst and either a powdered alkali metal hydroxide such as e.g. B. sodium or potassium hydroxide or a concentrated aqueous solution of the same, preferably in a temperature range from 20 ° C. to 120 ° C.

Suitable phase transfer catalysts are e.g. Trialkylbenzylammonium or tetraalkylammonium halides, hydroxides, hydrogen sulfates with preferably 1 to 12 C atoms in the alkyl radical or crown ether, such as e.g. 12-Crown-4, 15-Crown-5, 18-Crown-6 or Dibenzo-18-crown-6.

• Die Ausgangsverbindungen der Formel II, in der Ar und A die zu Formel I angegebenen Bedeutungen haben, sind teilweise bekannt; die nicht bekannten können in Analogie zu den bekannten hergestellt werden.

Production of the raw materials:

• Some of the starting compounds of the formula II in which Ar and A have the meanings given for formula I are known; the unknowns can be prepared in analogy to the known ones.

Process variant B), a compound of the formula IV in which E preferably denotes Br, J or trifluoroacetyloxy, methanesulfonyloxy, benzene-, nitrobenzene-, bromobenzene- or toluenesulfonyloxy and E ^I preferably denotes Cl or Br, with a compound of the formula III, in which M, R ¹ , g and Y have the meanings given, is reacted to form a compound of the formula V, is carried out under the same reaction conditions as given for variant A for the preparation of compounds of the formula I.

The preparation of compounds of the formula I by reacting compounds of the formula V with compounds of the formula VI is advantageously carried out in an inert solvent in the presence of a base, as indicated above for the first preparation process, preferably in a temperature range from 100 to 190.degree. The reaction is conveniently carried out in the presence of an alkali iodide such as e.g. Sodium or potassium iodide, optionally in an autoclave under pressure.

The reactions described above can expediently be carried out as a one-pot reaction by first reacting a compound of the formula VI with a compound of the formula III in the presence of a base in an inert solvent at 40 to 100 ° C. Subsequently, without isolating the compound of the formula V, a compound of the formula VI and, if appropriate, a further molar equivalent of a base and an alkali iodide (e.g. potassium iodide) are added and the mixture is heated to 100 to 190 ° C.

• Verbindungen der Formel IV, in der E und E' die zur Formel II für E angegebenen Bedeutungen haben, sind bekannt. Sie werden hergestellt, indem man eine Verbindung der Formel
  

Production of the raw materials:

• Compounds of the formula IV in which E and E 'have the meanings given for E in formula II are known. They are made by using a compound of the formula
  

in der E' Cl oder Br bedeutet und Ar die angegebenen Bedeutungen hat, mit 1-Brom-2,3-propandiol in einem inerten Lösungsmittel in Gegenwart einer starken Säure unter Bildung eines 1,3-Dioxolans nach für derartige Ketalisierungen bekannten Methoden umsetzt.XI converted into a reactive ester group in the usual way. For example, the compounds of the formula IV in which E 'is preferably Cl or Br and E is methanesulfonyloxy are prepared by using a compound of the formula XI in which Ar has the meanings given for formula I and E' is Cl or Br, with methanesulfochloride at -10 ° C to + 50 ° C appropriately in an inert solvent, in the presence of a base. Compounds of the formula IV in which E is, for example, bromine are obtained by reacting compounds of the formula XI (E ^{I =} Cl or Br) with bromination agents, such as, for example, PBr ₃ or POBr _3, in an inert solvent at 0 ° C. to 100 ° C. produced. Such connections can also be made in which is a compound of formula XII,

in which E 'denotes Cl or Br and Ar has the meanings indicated, with 1-bromo-2,3-propanediol in an inert solvent in the presence of a strong acid to form a 1,3-dioxolane by methods known for such ketalizations.

The compounds of formula XI are known.

Process variant C), in which a compound of the formula VII is reacted with a compound of the formula VIII to form a compound of the formula I, is generally carried out under the same conditions as the preparation of compounds of the formula IV (variant B) . The ketalization of ketones of the formula VII with glycerol derivatives of the formula VIII is advantageously carried out in a solvent mixture consisting of an inert solvent which forms an azeotropic mixture with water, e.g. Benzene, toluene, xylene, chlorobenzene or cyclohexane, and an alcohol, in the presence of a strong acid in a temperature range from 75 to 180 ° C. Advantageous in this ketalization are at least 2.5 equivalents of a strong acid (based on the azole compound of the formula VII) and, as alcohols, aliphatic alcohols with a bp between 75 ° and 150 ° C. and / or monoethers of lower diols between 100 ° and boil at 150 ° C.

• Die Verbindungen der Formel VII sind bekannt und können nach bekannten Methoden hergestellt werden.

Production of the raw materials:

• The compounds of formula VII are known and can be prepared by known methods.

Compounds of the formula VIII, in which R ¹ , g and Y have the meanings given for the formula I, are prepared by reacting compounds of the formula III with 1-halogeno-2,3-propanediol, in a manner analogous to that in Org. Synth. Collect. Vol. I, p. 296.

In process variant D), a compound of formula IX is mixed with a heterocyclic compound of formula X, preferably with a heterocyclic compound either of formula Xa ₁ , Xa ₂ , Xb ₁ , Xb ₂ , Xc, Xd ₁ , Xd ₂ , Xd ₃ , Xd ₄ , Xd5, Xd ₆ or Xd ₇ , in which E "in each case has the meanings given, advantageously in an inert organic solvent in a temperature range from 20 ° to 180 ° C, preferably from 50 ° to 120 ° C, implemented This reaction is advantageously carried out in the presence of a base, which is preferably used in an equimolar amount.

The synthesis of compounds of the formula I from the compounds of the formulas IX and X can also be carried out without addition of base. The reactants of formulas IX and X can be used in different molar ratios, i.e. either the compounds of the formula IX or those of the formula X can be used in excess, equimolar amounts are advantageously used.

Examples of suitable solvents are hydrocarbons, generally ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, or acetonitrile, butyronitrile, dimethylformamide or acetamide, acetone, 4-methyl-2-pentanone, methylene chloride, chloroform, dimethylsulfoxide, Anisole, chlorobenzene, tetrachlorethylene or mixtures of these solvents.

Suitable bases are those exemplified in process variant A).

The reaction can also be carried out under the conditions of a phase transfer reaction, as explained in the description of process variant A).

• Die Verbindungen der Formel IX sind z.T. bekannt; solche, die von den bekannten abweichende Bedeutungen für Ar haben und/oder bei denen g 1 oder 2 bedeutet, können in Analogie zu den bekannten hergestellt werden.

Production of the raw materials:

• Some of the compounds of the formula IX are known; Those which have different meanings for Ar and / or where g is 1 or 2 can be prepared analogously to the known ones.

Some of the compounds of the formula X, in which E "and Y have the meanings given, are known. This applies in particular to compounds of the formulas Xa ₁ and Xd ₁ -Xd ₇ with E" = Cl.

If the substituents R ² and R ⁶ -R ¹¹ on the heterocyclic compounds Xa ₁ , Xa ₂ , Xb ₁ , Xb ₂₉ Xc, Xd ₁ -Xd ₅ differ from known compounds and the substituents are largely inert, ie insensitive , These compounds or their precursors, in which the substituents R ² and R ⁶ -R ¹¹ , p and n have the meanings given, can be prepared analogously to the known compounds of these structures.

Compounds of the formula Xa ₁ with R ³ = hydrocarbyloxy and R ⁴ = H or Br are obtained by alkylation from the compounds of the formula Xa ₂ (R ^{5 =} H) corresponding to R ² and R ⁴ with conventional alkylating agents, such as alkyl iodides , Allyl or propargyl bromide, benzyl bromide or chloride or corresponding alkane or arylsulfonic acid esters, such as butyl mesylate or toluenesulfonic acid ethyl ester.

This alkylation generally results predominantly in the 0-alkylated compounds of the formula Xa ₁ with R ³ = hydrocarbyloxy in addition to smaller proportions of the corresponding N-alkylated compounds of the formula Xa ₂ with R ⁵ = Hydrocarbyl. This N-alkylation can take place on the N-1 or on the N-3. No distinction is made between these two structures in the compounds according to the invention. Therefore, two formulas are listed for the compounds of the formulas Xa ₂ and Xb ₂ , and for the heterocyclic radicals Y of the structure a ₂ and b ₂ . If compounds of the formula _Xa2 or Xb _{2 are used} as starting material for the preparation of compounds of the formula I in which the heterocyclic radical Y has the meanings a ₂ or b ₂ , they are, according to NMR spectra and TLC analysis uniform connections. This means that in the case of the compounds Xa ₂ and Xb ₂ , R ^{5 is} bound either to the N-1 or to the N-3, although, as already explained, no distinction is made between these two structures in a ₂ and b ₂ .

The resulting 0-alkyl compounds Xa (R ³ = hydrocarbyloxy) and N-alkyl compounds Xa ₂ (R ⁵ = hydrocarbyl) can be separated by column chromatography on silica gel or by fractional recrystallization.

To prepare the N-alkylated compounds of the formulas Xa ₂ and Xb ₂ , compounds of the formula Xa ₂ with R ⁵ = H and E "are preferably Cl or compounds of the formula Xb ₂ with R ⁵ and E" = H with dialkyl sulfates in aqueous alkaline solution Medium alkylated. As explained above, 0 and N-alkylated compounds are formed side by side, but with a higher proportion of N-alkylated compounds of the formulas Xa ₂ and Xb ₂ than in the alkylation with alkyl halides or sulfonic acid esters. This alkylation is preferably carried out using dimethyl sulfate, predominantly or almost exclusively obtaining N-methylpyrimidines of the formulas Xa ₂ and Xb ₂ with R ^{5 =} CH ₃ . The purification of these compounds, in particular the removal of 0-alkyl compounds, is carried out by column chromatography or by fractional Um crystallization. The following formula scheme I serves to illustrate these syntheses.

5-Bromomethyl-pyrimidines of the formulas Xb ₁ and Xb ₂ (E "= Br) are prepared starting from the corresponding 5-methyl-pyrimidines Xb ₁ and Xb ₂ (E" = H) by the action of N-bromosuccinimide ( NBS) (see formula scheme I).

Formula scheme I

Formelschema I, Forts.

Formula Scheme I, cont.

The compounds Xa ₂ with R ^{5 =} H and E "= Cl and Xb ₂ with R ⁵ and E" = H are known or can be prepared by known methods. Compounds of the formula Xa ₂ with R ⁴ and R ⁵ = H and E "= Cl can be converted into those with R ^{4 =} Br, R ⁵ = H and E" = Cl by the action of NBS.

Some compounds of the formula Xb with R ³ = 0-R "and E" = H, where R "in general means a hydrocarbon or a (substituted) phenyl radical within the meaning given for R ^{3 in} formula I, are known They are prepared by converting compounds Xb ₂ with R ⁵ and E "= H in a known manner by the action of phosphorus oxychloride (POC1 ₃ ) into the corresponding 4-chloropyrimidines of the formula Xb ₁ with R ^{3 =} Cl and E" = H and these are then reacted with a compound of the formula XI (cf. formula scheme I). The pyrimidines Xb ₁ thus obtained with R ³ = 0-R "and E" = H can, as already explained, be converted into the corresponding 5-bromomethyl with NBS -pyrimidines are transferred.

Some of the compounds Xc with E "= Cl and p = 0 are known; those in which R ⁷ -R ⁹ have different meanings from the known compounds can be prepared analogously to those described. Compounds of the formula Xc with p = 1 can be prepared by reacting tolylamidines of the formula XII, or their salts, by known methods with appropriately structured 1,3-diketones or 3-keto acid esters to form 2-tolylpyrimidines of the formulas XIIIa or XIIIb and converting them in accordance with known methods converts the pyrimidine derivative of the formula Xc required in each case, in which R ⁷ , R and R ^{9 have} the meanings indicated and E "= H" (cf. formula scheme II). Such 2- (tolyl) pyrimidines of the formula Xc with E "= H can be prepared by known methods, for example by bromination with NBS in compounds of Formula Xc with E "= Br or Cl and p = 1 are transferred (cf. Formula Scheme II).

Compounds of the formulas Xd ₁ , Xd ₂ , Xd ₃ , Xd ₄ and Xd ₅ , in which E "= Cl or Br, p = 0 and n = 0, 1 or 2, are known, those in which R ¹⁰ or R ^{11 has} a different meaning from the compounds described, can be prepared analogously to the known ones. Compounds of the formula Xd1 with E "= H and p = 1 are known. They are converted, for example by the action of NBS or by other known halogenation methods, into those in which E "denotes Cl or Br.

Compounds of the formulas Xd ₁ -Xd ₅ , in which E "= OH and p = 0, and R ¹⁰ , n and R ^{11 have} the meanings given, are known and can be prepared by known methods which, for example by the action of thionyl chloride, are converted into corresponding compounds of the formula Xd1-XdS with E "= Cl. Compounds of the formula Xd ₄ in which E" is H, n 1 or 2 and R ^{11 is} Cl or OCH ₃ can be prepared by the methods known for the synthesis of quinolines.

The compounds of the formula Xd ₅ with E "= H thus obtained are, by the action of NBS, in corresponding bromomethyl-quinolines of the formula Xd ₅ (E" = Br), in which _R ¹¹ and n have the meanings indicated and n is preferably 1, transferred (see formula scheme III below).

Depending on the process variant and the temperature range, the reaction times range from a few minutes to a few hours.

If necessary, the process products can be purified by recrystallization from a suitable solvent or solvent mixture or by column chromatography on silica gel.

The diastereomeric racemates (cis or trans form) of the compounds of formula I can be used in a conventional manner, e.g. separated by selective, fractional crystallization or column chromatography.

Since the stereochemical configuration is already specified in the intermediates of formula II, the Separation into the cis and trans form takes place at this stage or even earlier, for example at the stage of the intermediates of the general formula IV, or in the intermediates of the formula IX.

The cis and trans diastereomeric racemates can in turn be separated in a conventional manner into their optical antipodes cis (+), cis (-) or trans (+) and trans (-).

Process variants A, B and D are preferably used to prepare compounds of the formula I.

in der bedeuten:

• R¹ C₁-C₃-Alkyl, F oder Cl,
• g 0, 1 oder 2 und
• Y die folgenden heterocyclischen Reste
  
  
  
  oder c)
  
  in denen
• R² H, C₁-C₈-Alkyl, C₁-C₄-Alkoxy, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, J, Trifluormethyl, Methoxy, Ethoxy, Nitro oder C₁-C₄-Alkyl bedeuten, oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl-C₁-C₂-alkylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten, oder bei den heterocyclischen Resten a₁ und a₂, falls p Null bedeutet, darüberhinaus auch C₁-C₄-Alkylthio oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Benzylthiogruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten, bedeutet und
• R³ H, OH, Cl, C₁-C₄-Alkoxy oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Benzyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten, und beim heterocyclischen Rest b1 zusätzlich C₁-C₄-Alkyl oder eine unsubstituierte oder eine 1 oder 2 Substituenten tragende Phenyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅, CH₃ oder C₂H₅ bedeuten,
• R⁴ H, Cl, Br oder CN
• R⁵ H, C₁-C₄-Alkyl, Prop-2-en-1-yl, Prop-1-in-1-yl oder Benzyl
• p 0 oder 1 bedeutet, wobei in a₁, a₂ und c der Phenylenrest über die 2,3 oder 4-Position gebunden ist und
• R⁶ H, C₁-C₈-Alkyl, (C₃-C₆-Cycloalkyl)-C₁-C₃-alkyl, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, J, OCH₃, OC₂H₅, 1.2--O-CH₂-O-, CF₃ oder C₁-C₄-Alkyl bedeuten, eine unsubstituierte oder im Phenylrest durch OCH₃, OC₂H₅, 1.2- O-CH₂-O-, CF₃, F, Cl oder C₁-C₄-Alkyl substituierte Phenyl-C₁-C₂-alkylgruppe, oder CF₃, und
• _R ⁷ und _R ⁸ unabhängig voneinander H, C₁-C₈-Alkyl, C₁-C₄-Alkoxy oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl- oder Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃ oder OC₂H₅ bedeuten, und wobei R⁷ darüberhinaus auch OH bedeuten kann, und
• _R ⁹ H, Cl, Br oder CN bedeutet, oder
  
  oder
  
  oder
  
  in denen
• p 0 oder 1,
• R¹⁰ Cl, Br, OCH₃, OC₂H₅, ^CH ₃ oder C2H5,
• n 0, 1 oder 2 bedeutet, wobei R¹⁰ in d₁ in 3,4,5 und/ oder 6-, in d₂ in 2,4,5 und/oder 6- und in d₃ in 2,3, 5 und/oder 6-Stellung steht, und
• R¹¹ Cl, OCH₃, CH₃ oder C₂H₅ bedeutet und in d₄ und d₅ in einer bzw. zwei der freien Positionen steht, und der heterocyclische Rest d₄ über die 2,3 oder 4-Stellung und der heterocyclische Rest d₅ über die 5,6,7 oder 8-Stellung und die Phenyleneinheit im Rest d₁ über die 2,3 oder 4-(para)-Stellung gebunden ist, bedeutet,

sowie deren Säureadditionssalze.The invention further relates to compounds of the formula IIIa,

in which mean:

• R ¹ C ₁ -C ₃ alkyl, F or Cl,
• g 0, 1 or 2 and
• Y the following heterocyclic radicals
  
  
  
  or c)
  
  in which
• R ² H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F, Cl, Br, J, trifluoromethyl, methoxy Mean ethoxy, nitro or C ₁ -C ₄ alkyl, or an unsubstituted or a phenyl C ₁ -C ₂ alkyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be the same or different and F, Cl, Br , OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , or in the case of the heterocyclic radicals a ₁ and a ₂ , if p is zero, furthermore also C ₁ -C ₄ -alkylthio or an unsubstituted or one in the phenyl radical 1 or 2 substituent-bearing benzylthio group, where the substituents can be the same or different and are F, Cl, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , means and
• R ³ H, OH, Cl, C ₁ -C ₄ alkoxy or an unsubstituted or a benzyloxy group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , and in the heterocyclic radical b1 additionally C ₁ -C ₄ alkyl or an unsubstituted or a 1 or 2 substituent-bearing phenyloxy group, where the substituents can be the same or different and F, Cl, Br , OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ ,
• R ⁴ H, Cl, Br or CN
• R ⁵ H, C ₁ -C ₄ alkyl, prop-2-en-1-yl, prop-1-in-1-yl or benzyl
• p denotes 0 or 1, where in a ₁ , a ₂ and c the phenylene radical is bonded via the 2,3 or 4 position and
• R ⁶ H, C ₁ -C ₈ alkyl, (C ₃ -C ₆ cycloalkyl) -C ₁ -C ₃ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, the substituents being identical to or can be different and mean F, Cl, Br, J, OCH ₃ , OC ₂ H ₅ , 1.2 - O-CH ₂ -O-, CF ₃ or C ₁ -C ₄ alkyl, an unsubstituted or in the phenyl radical by OCH ₃ , OC ₂ H ₅ , 1.2-O-CH ₂ -O-, CF ₃ , F, Cl or C ₁ -C ₄ alkyl-substituted phenyl-C ₁ -C ₂ alkyl group, or CF ₃ , and
• _R ⁷ and _R ⁸ independently of one another are H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or an unsubstituted or a phenyl or benzyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ or OC ₂ H ₅ , and where R ^{7 can} also mean OH, and
• _R ⁹ denotes H, Cl, Br or CN, or
  
  or
  
  or
  
  in which
• p 0 or 1,
• R ¹⁰ Cl, Br, OCH ₃ , OC ₂ H ₅ , ^CH ₃ or C2H5,
• n denotes 0, 1 or 2, where R ¹⁰ in d ₁ in 3,4,5 and / or 6-, in d ₂ in 2,4,5 and / or 6- and in d ₃ in 2,3, 5 and / or 6-position, and
• R ^{11 is} Cl, OCH ₃ , CH ₃ or C ₂ H ₅ and is in d ₄ and d ₅ in one or two of the free positions, and the heterocyclic radical d ₄ via the 2,3 or 4 position and the heterocyclic Residue d ₅ via the 5,6,7 or 8-position and the phenylene unit in the rest d ₁ is bonded via the 2,3 or 4- (para) position, means

as well as their acid addition salts.

• _R ¹ CH₃ oder ^C ₂ ^H ₅
• g 0 oder 2
• Y
• zu den heterocyclischen Resten a₁, a₂, b₁, b₂ und c:
• R² H, C₁-C₄-Alkyl, CH₃0 oder eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl- oder eine Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br oder OCH3 bedeuten,
• R³ H oder C₁-C₄-Alkoxy und beim Rest b₁ zusätzlich eine unsubstituierte oder eine 1 oder 2 Substituenten tragende Phenyloxygruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃ oder OC₂H₅ bedeuten,
• R⁴ H oder CN
• _R ^{5 CH} ₃
• p 0 oder 1
• R⁶ H, C₁-C₈-Alkyl, (C₅-C₆-Cycloalkyl)-C₁-C₂-alkyl, eine unsubstituierte oder 1 oder 2 Substituenten tragende Phenylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl, Br, OCH₃, OC₂H₅ oder CF₃ bedeuten, eine unsubstituierte oder im Phenylrest durch OCH₃, CF₃, F oder Cl substituierte Benzylgruppe oder CF₃,
• R⁷, R⁸ unabhängig voneinander C₁-C₈-Alkyl, C₁-C₄-Alkoxy oder eine unsubstituierte oder eine im Phenylrest durch F, Cl, OCH₃ oder OC₂H₅ substituierte Phenyl- oder Benzylgruppe und R⁷ darüber hinaus auch H oder OH
• R⁹ H oder CN
  zu den heterocyclischen Resten d₁, d₂, d₃, d₄, d₅, d₆ und d₇:
  • p 0 oder 1,
  • _R ¹⁰ Cl, CH₃ oder C₂H₅,
  • n 0 oder 1, wobei R¹⁰ in d₃ bevorzugt in 2-Stellung steht, und
  • _R ¹¹ Cl, wobei die Phenyleneinheit im Rest d₁ bevorzugt über die 4-Stellung gebunden ist.

Compounds of the formula IIIa are preferred in which at least one of the substituents or indices R ¹ , g, Y, R ² -R ¹¹ , p and n has the following meanings:

• _R ¹ CH ₃ or ^C ₂ ^H ₅
• g 0 or 2
• Y
• to the heterocyclic radicals a ₁ , a ₂ , b ₁ , b ₂ and c:
• R ^{2 is} H, C ₁ -C ₄ alkyl, CH ₃ 0 or an unsubstituted or a phenyl group carrying 1 or 2 substituents or a phenyl group, or a benzyl group, where the substituents can be identical or different and denote F, Cl, Br or OCH3 ,
• R ³ H or C ₁ -C ₄ alkoxy and, in the case of the radical b _1, additionally an unsubstituted or a 1 or 2 substituent-bearing phenyloxy group, where the substituents can be identical or different and F, Cl, Br, OCH ₃ or OC ₂ H ₅ mean,
• R ⁴ H or CN
• _R ^{5 CH} ₃
• p 0 or 1
• R ⁶ H, C ₁ -C ₈ alkyl, (C ₅ -C ₆ cycloalkyl) -C ₁ -C ₂ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F , Cl, Br, OCH ₃ , OC ₂ H ₅ or CF ₃ , an unsubstituted or substituted in the phenyl radical by OCH ₃ , CF ₃ , F or Cl or CF ₃ ,
• R ⁷ , R ⁸ independently of one another are C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or an unsubstituted or phenyl or benzyl substituted by F, Cl, OCH ₃ or OC ₂ H _{5 in the} phenyl radical group and R ⁷ also H or OH
• R ⁹ H or CN
  for the heterocyclic radicals d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and d ₇ :
  • p 0 or 1,
  • _R ¹⁰ Cl, CH ₃ or C ₂ H ₅ ,
  • n is 0 or 1, where R ¹⁰ in d _{3 is} preferably in the 2 position, and
  • _R ¹¹ Cl, the phenylene unit in the rest d ₁ preferably being bonded via the 4-position.

• _R ^{1 CH} ₃
• g 0 oder 2
• Y
• zu den heterocyclischen Resten a₁, a₂, ^b ₁, ^b ₂ und c:
• _R ² eine unsubstituierte oder eine im Phenylrest 1 oder 2 Substituenten tragende Phenyl- oder Benzylgruppe, wobei die Substituenten gleich oder verschieden sein können und F, Cl oder OCH₃ bedeuten, und beim Rest b₁ zusätzlich C₁-C₄-Alkyl
• R³ _H und beim Rest b₁ zusätzlich eine unsubstituierte oder durch F, Cl, OCH₃ oder OC₂H₅ substituierte Phenyloxygruppe
• R⁴ H
• R^{5 CH} ₃
• p bei den heterocyclischen Resten a₁ und a₂ 0 oder 1 und bei dem heterocyclischen Rest c 1
• R⁶ C₁-C₈-Alkyl, (C₅-C₆-Cycloalkyl)-C₁-C₂-alkyl, eine unsubstituierte oder durch F, Cl, OCH₃ oder OC₂H₅ substituierte Phenylgruppe, eine unsubstituierte oder im Phenylrest durch F, Cl oder OCH₃ substituierte Benzylgruppe oder CF₃
• R⁷, R⁸ unabhängig voneinander C₁-C₃-Alkyl oder eine unsubstituierte oder eine im Phenylrest durch F, Cl oder OCH₃ substituierte Phenyl- oder Benzylgruppe und R⁷ darüber hinaus auch H oder C₁-C₄-Alkoxy
• _R ⁹ _H
• zu den heterocyclischen Resten _d1, _d2, d₃, d₄₉ d₅, d₆ und d₇:
  • p 1,
• n 0,
  wobei der Rest d₄ bevorzugt über die 2-Stellung und der Rest d₅ bevorzugt über die 6- oder 7-Stellung gebunden ist.

Compounds of the formula III a in which at least one of the substituents or indices has the following meanings are particularly preferred:

• _R ^{1 CH} ₃
• g 0 or 2
• Y
• to the heterocyclic radicals a ₁ , a ₂ , ^b ₁ , ^b ₂ and c:
• _R ^{2 is} an unsubstituted or a phenyl or benzyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and denote F, Cl or OCH ₃ , and in the radical b ₁ additionally C ₁ -C ₄ -alkyl
• R ³ _H and in the case of the radical b ₁ additionally an unsubstituted or substituted by F, Cl, OCH ₃ or OC ₂ H ₅ phenyloxy group
• R ⁴ H
• R ^{5 CH} ₃
• p for the heterocyclic radicals a ₁ and a ₂ 0 or 1 and for the heterocyclic radical c 1
• R ^{6 is} C ₁ -C ₈ alkyl, (C ₅ -C ₆ cycloalkyl) -C ₁ -C ₂ alkyl, an unsubstituted or substituted by F, Cl, OCH ₃ or OC ₂ H ₅ , an unsubstituted or in the phenyl radical substituted by F, Cl or OCH _3, benzyl group or CF ₃
• R ⁷ , R ⁸ independently of one another are C ₁ -C ₃ alkyl or an unsubstituted or phenyl or benzyl group substituted by F, Cl or OCH ₃ in the phenyl radical, and R ⁷ also H or C ₁ -C ₄ alkoxy
• _R ⁹ _H
• for the heterocyclic residues _d1 , _d2 , d ₃ , d ₄₉ d ₅ , d ₆ and d ₇ :
  • p 1,
• n 0,
  where the residue d _{4 is} preferably bonded via the 2-position and the residue d ₅ preferably via the 6- or 7-position.

The compounds of the formula IIIa, in which R ¹ , g and Y have the meanings given, are new and are valuable intermediates for the preparation of the compounds of the formula I which have a strong antifungal and fungicidal action. Some of the compounds of the formula IIIa also have an antifungal action and fungicide. Some of the compounds of the formula IIIa also show pharmacological effects, for example effects on the cardiovascular system.

in der R¹ und g die zu Formel I angegebenen Bedeutungen haben oder ein Salz dieser Verbindung, mit einer Verbindung der Formel X,

• in der E" Cl, Br, J, Acyloxy, wie Acetoxy oder Benzoyloxy, Alkylsulfonyloxy, wie Methansulfonyloxy, oder Arylsulfonyloxy, wie Benzol-, Nitrobenzol-oder Toluolsulfonyloxy, bedeutet, und
• Y die zur Formel I unter a₁, a₂, b₁, b₂, c, d₁, d₂, a₃, d₄, d₅₂ d₆ und d₇ angegebenen Bedeutungen hat,

umsetzt und gegebenenfalls die erhaltenen Verbindungen der Formel IIIa mit anorganischen oder organischen Säuren in ihre Säureadditionssalze überführt.The invention also relates to a process for the preparation of compounds of the formula IIIa, which is characterized in that a compound of the formula XIV,

in which R ¹ and g have the meanings given for formula I. have or a salt of this compound, with a compound of formula X,

• in which E "denotes Cl, Br, J, acyloxy, such as acetoxy or benzoyloxy, alkylsulfonyloxy, such as methanesulfonyloxy, or arylsulfonyloxy, such as benzene, nitrobenzene or toluenesulfonyloxy, and
• Y has the meanings given for the formula I under a ₁ , a ₂ , b ₁ , b ₂ , c, d ₁ , d ₂ , a ₃ , d ₄ , d ₅₂ d ₆ and d ₇ ,

reacted and, if appropriate, the compounds of the formula IIIa obtained are converted into their acid addition salts using inorganic or organic acids.

• a) eine Verbindung der Formel Xa₁ oder der Formel Xa₂,
  
  in denen R^2-R⁵ die zu Formel I angegebenen Bedeutungen haben und E" Cl oder Br bedeutet, oder
• b) eine Verbindung der Formel Xb₁ oder der Formel Xb₂
  
  in denen R², R³, R und R⁶ die zu Formel I angegebenen Bedeutungen haben und E" Br bedeutet, oder
• c) eine Verbindung der Formel Xc,
  
  in der R⁷, R⁸, R⁹ und p die zu Formel I angegebenen Bedeutungen haben und E" Cl oder Br bedeutet, oder
• d) eine Verbindung der Formel Xd₁, der Formel Xd₂, der Formel Xd₃, der Formel Xd₄, der Formel Xd₅, der Formel Xd₆ oder der Formel Xd₇
  
  
  
  in denen _R ¹⁰, _R ¹¹, p und n die zu Formel I angegebenen Bedeutungen haben und E" Cl oder Br bedeutet.

Are preferably used for the reaction according to the invention with compounds of the formula XIV either

• a) a compound of the formula Xa ₁ or of the formula Xa ₂ ,
  
  in which R ^2- R ^{5 have} the meanings given for formula I and E "is Cl or Br, or
• b) a compound of the formula Xb ₁ or of the formula Xb ₂
  
  in which R ² , R ³ , R and R ^{6 have} the meanings given for formula I and E "Br", or
• c) a compound of the formula Xc,
  
  in which R ⁷ , R ⁸ , R ⁹ and p have the meanings given for formula I and E "is Cl or Br, or
• d) a compound of the formula Xd ₁ , the formula Xd ₂ , the formula Xd ₃ , the formula Xd ₄ , the formula Xd ₅ , the formula Xd ₆ or the formula Xd ₇
  
  
  
  in which _R ¹⁰ , _R ¹¹ , p and n have the meanings given for formula I and E "is Cl or Br.

The process according to the invention for the preparation of compounds of the formula IIIa is advantageously carried out in an inert organic solvent in a temperature range from 20 ° to 180 ° C., preferably from 50 ° to 120 ° C., advantageously in the presence of a base, which is preferably used in an equivalent amount , carried out. Are for the procedure ren salts of the compounds of formula XIV, then the stoichiometric amount of base corresponding to the salt content is added. A further proportion of base can then optionally be used.

The synthesis of compounds of the formula IIIa from the compounds of the formulas XIV and X can, if the compounds XIV are not used as a salt, also be carried out without addition of base. The reactants of formulas XIV and X can be used in different molar ratios, i.e. either the compounds of formula XIV or those of formula X can be used in excess, equimolar amounts are advantageously used.

Examples of solvents are hydrocarbons, generally ethers, such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, or acetonitrile, butyronitrile, dimethylformamide or acetamide, acetone, 4-methyl-2-pentanone, methylene chloride, chloroform, dimethylsulfoxide, anisole , Chlorobenzene, tetrachlorethylene or mixtures of these solvents in question.

Suitable bases are those exemplified in process variant A).

Depending on the temperature range, the reaction times range from a few minutes to a few hours.

If necessary, the process products can be purified by recrystallization from a suitable solvent or solvent mixture or by column chromatography on silica gel.

• Die Verbindung der Formel XIV mit g=0 ist bekannt. Verbindungen der Formel XIV, bei denen g 1 oder 2 bedeutet und R¹ die zu Formel I angegebenen Bedeutungen hat, werden in Analogie zu den bekannten Verbindungen durch Umsetzung von entsprechenden 4-Methoxy-Anilinen mit Bis-(2-Chlorethyl)-amin und anschließender Phenolether-Spaltung mit konz. wäßriger Bromwasserstoffsäure hergestellt.

Production of the raw materials:

• The compound of formula XIV with g = 0 is known. Ver Bonds of formula XIV, in which g is 1 or 2 and R ^{1 has} the meanings given for formula I, are made in analogy to the known compounds by reacting corresponding 4-methoxy-anilines with bis- (2-chloroethyl) amine and subsequent phenol ether cleavage with conc. aqueous hydrobromic acid.

The preparation of the compounds of the formula X, in which E "and Y have the meanings given, provided that they are not known, has already been described in process variant D) for the preparation of compounds of the formula I.

The compounds of formula I and their acid addition salts are valuable drugs. They have an antimicrobial effect and are particularly suitable for the prevention and treatment of fungal infections in humans and in various types of mammals.

The new compounds are very effective in vitro against skin fungi, e.g. Trichophyton mentagrophytes, Microsporum canis, Epidermophyton floccosum; against mold, e.g. Aspergillus niger or against yeasts, e.g. Candida albicans, C. tropicalis, Torulopsis glabrata and Trichosporon cutaneum or against protozoa like Trichomonas vaginalis or T. fetus, or against gram-positive and gram-negative bacteria.

Also in vivo, e.g. in experimental kidney candidiasis of the mouse, the compounds have a very good systemic effect after oral or parenteral use, e.g. against Candida albicans. There is also a very good effect against various pathogens of skin mycoses (e.g. Trichophyton mentagrophytes) on guinea pigs after oral, parenteral or local use.

• Dermatomykosen und Systemmykosen durch Trichophyton mentagrophytes und andere Trichophytonarten, Mikrosporonarten, Epidermophyton floccosum, Sproßpilze und biphasische Pilze sowie Schimmelpilze hervorgerufen.

Indications for use in human medicine include:

• Dermatomycoses and system mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, microsporon species, Epidermophyton floccosum, shoots and biphasic fungi as well as molds.

• Alle Dermatomykosen und Systemmykosen, insbesondere solche, die durch die oben genannten Erreger hervorgerufen werden.

Indications in veterinary medicine can include the following:

• All dermatomycoses and system mycoses, especially those caused by the pathogens mentioned above.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and processes for producing these preparations.

Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Dosage forms include, for example, tablets, dragees, capsules, pills, aqueous solutions, suspensions and emulsions, optionally sterile injectable solutions, non-aqueous emulsions, suspensions and solutions, ointments, creams, pastes, lotions, sprays, etc.

The therapeutically active compounds should advantageously be present in the pharmaceutical preparations listed above in a concentration of about 0.01 to 99.0, preferably of about 0.05 to 50,% by weight of the total mixture.

In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in human and veterinary medicine for preventing, ameliorating and / or curing the diseases mentioned above.

The active ingredients or the pharmaceutical preparations can be applied locally, orally, parenterally, intraperitoneally and / or rectally.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of from about 0.05 to about 200, preferably 0.1 to 100, in particular 0.5 to 30 mg / kg body weight per 24 hours, if necessary in the form of several single doses to achieve the desired results. The total amount is administered in 1 to 8, preferably in 1 to 3 individual doses.

However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval, within which the Adm submission takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The optimum dosage and type of application of the active ingredients required in each case can easily be determined by any person skilled in the art on the basis of his specialist knowledge.

The new compounds of formula I are also suitable for the treatment of protozoan diseases in humans and animals such as z. B. caused by infections with Trichomonas vaginalis and Entamoeba histolytica and by Trypanosoma cruzi, Leishmania donovani.

The new compounds can be used orally or locally. Oral use takes place in customary pharmaceutical preparations, e.g. B. in the form of tablets or capsules.

The compounds of formula I are also effective as biocides. They are particularly characterized by their fungicidal activity in phytopathogenic fungi. Even fungal pathogens that have already penetrated the plant tissue can be successfully combated. This is particularly important and advantageous in the case of those fungal diseases which can no longer be effectively combated with the usual fungicides after infection has occurred. The spectrum of activity of the new compounds covers a variety of different phytopathogenic fungi, e.g. Piricularia oryzae, Plasmopara viticola, various types of rust, but especially Ventaria inaequalis, Cercospora beticola and powdery mildew in fruit, vegetable, cereal and ornamental plants.

The new compounds of formula I are also suitable for use in technical fields, for example as wood preservatives, as preservatives in An line-colored, in cooling lubricants for metalworking or as a preservative in drilling and cutting oils.

The new compounds can be used as wettable powders, emulsifiable concentrates, sprayable solutions, dusts, mordants, dispersions, granules or microgranules in the customary preparations.

The following examples serve to explain the invention in more detail without restricting it.

Examples of the manufacturing process variant A) example 1

To a solution of 2.26 g (6 m mol) of 4- (4- (4-hydroxyphenyl) piperazin-1-ylmethyl) -6-methoxy-2-phenyl-pyrimidine in 20 ml abs. NN-dimethylformamide (DMF) was added to 0.184 g (6.13 m mol) of 80% sodium hydride oil dispersion. After the evolution of hydrogen had subsided, a solution of 2.49 g (6.1 m mol) of 2-S (R) - (2.4-dichlorophenyl) -2- (1.2.4-triazol-1-ylmethyl) -4- R, (S) -methanesulfonyloxymethyl-1,3-dioxolane (cis form) in 16 ml abs. DMF was added and the mixture was stirred at 100 ° C. for 4 hours. The DMF was then distilled off in vacuo (3-10 mbar) on a rotary evaporator, the residue was mixed with 50 ml of water and 50 ml of CH ₂ Cl ₂ , shaken, the phases were separated and the aqueous phase was extracted three more times with CH ₂ C1 _2nd The combined CH ₂ C1 ₂ extracts were dried with MgS0 ₄ , filtered and evaporated in vacuo. The residue (5.5 g) was dissolved in 12 ml of methanol, whereupon crystalline precipitate separated out. This was isolated (3.02 g) and recrystallized from a 2: 3 mixture of CH ₃ CN and CH ₂ Cl ₂ by evaporating a large part of the CH ₂ C1 ₂ at normal pressure after dissolving at boiling temperature. Upon cooling, pure 2-S, (R) - (2.4-dichlorophenyl) -2- (1.2.4-triazol-1-ylmethyl) -4-R, (S) - {4- (4- (4-methoxy -2-phenyl-pyrimidin-6-ylmethyl) piperazin-1-yl) phenoxymethyl] -1,3-dioxolane (cis form). After suction filtration, washing with CH ₃ CN and drying, 2.75 g (66.6% yield) of this compound were obtained; Mp 146-47 ° C, elemental analysis: C ₃₅ H ₃₅ Cl ₂ N ₇ O ₄ (MW 688.64) calc. C 61.05, H 5.12, Cl 10.30, N 14.24; Found C 60.8, H 5.2, Cl 10.3, N 14.3%; the ¹ H-NMR spectrum (CDCl ₃ ) confirms the structure.

Example 2

According to Example 1, in each case using the methanesulfonates IIb and IIc (cf. Table 1) and the corresponding compounds of the formula IIIa (cf. Table 1), the following compounds listed in Table 1 were obtained. of formula I (Ar: 2,4-dichlorophenyl, cis form).

Example 3

To a solution of 1.73 g (5 m mol) of 4- (4-hydroxyphenyl) -1- (4- (2-pyridyl) benzyl) piperazine in 20 ml abs. DMF was added at room temperature to 0.58 g (5.15 m mol) of potassium tert-butoxide, the mixture was stirred for 8 minutes, and then a solution of 2.04 g (5 m mol) of IIb was added (see Ex. 2, Tab. 1) in 15 ml abs. 1,2-dimethoxyethane (DME) and the mixture was stirred for 5 hours at 91-92 ° C. The solvents were then stripped off in vacuo, the residue was taken up in water / CH ₂ C1 ₂ and, after thorough mixing, the phases were separated. The aqueous phase was extracted twice more with CH ₂ C1 ₂ . The combined CH ₂ C1 ₂ extracts were dried, filtered and evaporated. The remaining residue (2.9 g) crystallized from methanol. After suction filtration, washing with ice-cold methanol and drying, 2.31 g (= ̂ 70.4% yield) of pure cis-2- (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4- [4 - (4- (4- (2-pyridyl) benzyl) piperazin-1-yl) phenoxymethyl I-1,3-dioxolane, mp 89-90 ° C; Analysis: ^C ₃₆ ^H ₃₅ ^C1 ₂ ^N ₅ ⁰ ₃ ( ^MG 656.63) calc. C 65.85 H 5.37 N 10.67; Found: C 65.7 H 5.3 N. 10.5.

Example 4

Following the same procedure as described in Example 3, also on a 5 m mol scale, was used the same piperazine derivative as an intermediate and when using IIb (cf. Ex. 2, Tab. 1) and when using 0.203 g (5.2 m mol) of sodium amide, instead of potassium tert-butoxide as the base otherwise the same reaction conditions as described in Example 3, cis-2- (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4- [4- (4- (4- (2-pyridyl) benzyl) piperazine -1-yl) -phenoxy-methylJ-1,3-dioxolane, 2.19 g (= ̂ 66.8% yield), mp. 88-90 ° C, obtained.

Example 5

To a solution of 1.79 g (4.7 m mol) of 5- (4- (4-hydroxyphenyl) piperazin-1-ylmethyl) -2- (4-chlorophenyl) pyrimidine in 19 ml abs. DMF was added at room temperature 0.145 g (4.83 moles) of 80% NaH oil dispersion. After the evolution of hydrogen had subsided, a solution of 1.974 g (4.85 m mol) IIb (cf. Ex. 2, Tab. 1) in 15 ml abs. DMF was added and the mixture was then stirred at 102-104 ° C. for 2 hours. It was then worked up as described in Example 1. The CH ₂ C1 ₂ extract residue (3.02 g) crystallized from methanol. After suction filtration, washing with methanol and drying, 2.73 g (= ̂ 84% yield) of pure 2-S, (R) - (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-R, (S) - [4- (4- (2- (4-chlorophenyl) pyrimidin-5-ylmethyl) piperazin-1-yl) phenoxymethylJ-1,3-dioxolane (cis form); Mp 153-54 ° C, analysis: C ₃₅ H ₃₃ Cl ₃ N ₆ O ₃ (MW 692.07) calc. C 60.74, H 4.81 N 12.14; Found C 60.5 H 4.6 N 12.1%; the ¹ H-NMR spectrum (CDCI3) confirms the structure.

If the procedure is basically the same as that described above, instead of dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide or N-methylpyrrolidone- (2), and mixtures of these solvents with, for example, Tetrahydrofuran, dioxane, 1,2-dimethoxyethane or acetonitrile can be used.

Example 6

According to Example 5, in each case using the methanesulfonates IIb or IIc (see Table 1) and the corresponding compounds of the formula IIIb (Y see Table 2), the following compounds of the formula I (Ar: 2.4- Dichlorophenyl, cis form).

If the compounds of the formula I could not be purified by crystallization or recrystallization after working up, the CH ₂ Cl ₂ extract residue was in each case on a silica gel S (Riedel-de Haen, particle size 0.063-0.2 mm) -CH ₂ Cl ₂ column chromatographed. One eluted fractionally with CH ₂ C1 ₂ and further with CH ₂ Cl ₂ / C ₂ H ₅ OH mixtures successively increasing C ₂ H ₅ 0H content (up to max. 5 vol% C ₂ H ₅ 0H) and the fractions were checked by thin layer chromatography (DC) (precast DC plates, silica gel 60, F 254, Merck). Compounds indicated with ( ^* ) in Table 2 were thus obtained in pure form by column chromatography.

Example 7

A mixture of: 1.37 g (3.8 m mol) of 4- (4-hydroxyphenyl) -1- (4- (4-methyl-pyrimidin-2-yl) benzyl) piperazine, 35 ml of toluene, 5 , 5 ml of 50% sodium hydroxide solution, 1.55 g (3.8 m mol) of IIb (cf. Table 1) and 0.29 g of tetrabutylammonium bromide were stirred vigorously at 100 ° C. for 3 hours. The phases were then separated and the conc. Washed out sodium hydroxide solution twice with ether. The combined organic phases were washed twice with water, dried, filtered and i. Vac. evaporated. The extract residue (2.35 g) was, as described in Example 6, on a silica gel S (Riedel-de Haen, particle size 0.063-0.2 mm) -CH ₂ C1 ₂ column (φ 2.1 cm, height 28 cm) chromatographed. The DC-uniform, pure fractions were combined and evaporated in vacuo. 2.17 g (= ̂ 85.1% yield) of pure cis-2- (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-L4- (4- (4- (4-methyl -pyrimidin-2-yl) -benzyl) -piperazin-1 _- yl) -phenoxy-methylJ-1,3-dioxolane as a highly viscous oil; Analysis: C ₃₆ H ₃₆ Cl ₂ N ₆ O ₃ (MG ₆₇₁ , _{65) calc. C 64, 38, 5 H, 4} 0, Cl 10.56, N 12.51; Found C 64.2, H 5.5, Cl 10.7, N 12.3%.

Example 8

Using the same procedure as described in Example 7, starting from IIb or IIc (see Table 1) and in each case the corresponding compound IIIb (Y see Table 3), the compounds of the formula I listed in Table 3 (g = 0 or 2, R ¹ H or CH ₃ in the 2.6 position).

Example 9 (Salt Formation)

A solution of 580 mg (0.864 mol) of 2-S, (R) - (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-R, (S) - [4- (4- (4th -methyl-2-phenyl-pyrimidin-5-ylmethyl) -piperazin-1-yl) -phenoxymethyl] -1,3-dioxolane (cis form) (see Example 6, No. 2.5) in 20 ml CH ₂ Cl ₂ was mixed with 0.29 ml of a 6 m solution of HC1 in ether, whereupon crystalline precipitate separated out. The mixture was evaporated in vacuo, the remaining crystalline residue was boiled with 10 ml of ethyl acetate and, after cooling to about 7 ° C., suction filtered and dried. This gave 620 mg (= ̂ 96% yield of dihydrochloride) cis-2- (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-14- (4- (4-methyl-2-phenyl-pyrimidine) -5-ylmethyl) -piperazin-1-yl) -phenoxymethylJ-1,3-dioxolane dihydrochloride, mp. 180-81 ° C, analysis: C ₃₆ H ₃₈ Cl ₄ N ₆ O ₃ (MW 744.58), calc. Cl (total) 19.04, CL ^⊖ 9.52, found Cl (total) 18.8, Cl ^⊖ 9.6%.

Examples of the manufacturing process variant B) Example 10

• a) To a solution of 7.21 g (20 m mol) of 5- (4- (4-hydroxyphenyl) piperazin-1-ylmethyl) -4-methyl-2-phenyl-pyrimidine in 70 ml abs. NN-dimethylformamide (DMF) was added at room temperature (with cooling) to 0.60 g of 80% sodium hydride oil dispersion. After the evolution of hydrogen had ended, a solution of 8.40 g (20 mol) of cis-2-bromomethyl-2- (2.4-dichlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolane (cis and trans relates to the bromomethyl and methanesulfonyloxymethyl group in the 2- or 4-position of the dioxolane ring) in 25 ml abs. DMF was added dropwise and the mixture was stirred at 60-63 ° C. for 8 hours. The subsequent work-up and column chromatography were carried out in the same manner as described in Examples 1 and 6. Chromatographic purification was carried out on a silica gel S-CH ₂ C1 _{2 /} petroleum ether 3: 1 column (φ 3.6 cm, H = 37 cm) eluting with CH ₂ Cl ₂ / petroleum ether 3: 1, CH ₂ C1 ₂ and CH ₂ C1 ₂ / C ₂ H ₅ 0H mixtures (increasing C ₂ H ₅ OH content, up to a maximum of 3% by volume). 8.76 g (64.0% of theory) of cis-2-bromomethyl-2- (2.4-dichlorophenyl) -4- [4- (4- (4-methyl-2-phenyl-pyrimidine-5) were obtained -ylmethyl) -piperazin-1-yl) -phenoxy-methylj-1,3-dioxolane as a highly viscous oil, analysis: C ₃₃ H ₃₃ BrCl ₂ N ₄ O ₃ ( ⁶⁸ 4.49) calc. C 57.91, H 4.86, Br 11.6 ₈ , Cl 10.36, N 8.19; Found C 57.3, H 4.6, Br 11.9, Cl 10.0, N 7.8%.
• b) To a solution of 0.85 g (12.5 m mol) imidazole in 25 ml abs. N.N-dimethylacetamide was added 0.375 g (12.5 m mol) of 80% NaH oil dispersion. After the evolution of hydrogen had ended, a solution of 6.85 g (10 m mol) of the bromomethyl compound prepared under a) in 10 ml of abs. N.N-dimethylacetamide was added dropwise and then boiled under reflux for 24 hours. It was then worked up as described in Example 1.

The dimethylacetamide was distilled off in an oil pump vacuum on a rotary evaporator. The CH ₂ Cl ₂ extract residue (6.8 g) was chromatographed on a silica gel S-CH ₂ C1 ₂ column (φ 2.6 cm, H 40 cm) as described in Example 6. This gave 2.55 g of highly enriched substance which crystallized from methanol 2.18 g (= ̂ 32.5% yield) of pure cis-2- (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4- [4- (4- (4-methyl-2-phenyl-pyrimidin-5-ylmethyl) piperazin-1-yl) phenoxymethylJ-1,3-dioxolane; Mp 160-61 ° C; Analysis: Found C 64.2, H 5.3, N 12.3% (calculated values see Example 6 No. 2.5).

Example 11

Following the same procedure as described in Example 10a, starting from 15.5 m mol of 4- (4-hydroxyphenyl) -1- (4- (4-methyl-pyrimidin-2-yl) benzyl) piperazine, the corresponding Amount of NaH and 15.5 moles of cis-2-bromomethyl-2- (2.4-dichlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolane, 6.92 g (= ̂ 65.2% of theory) cis-2- Bromomethyl _- 2- (2.4-dichlorophenyl) -4- [4- (4- (4- (4-methyl-pyrimidin-2-yl) benzyl) piperazin-1-yl) phenoxymethyl] -1,3-dioxolane as obtained viscous oil; Analysis: C ₃₃ H ₃₃ BrCl ₂ N ₄ O ₃ (684.49) ^B er. C 57.91, H 4.86, Br 11.68, Cl 10.36, N 8.19; Found C 56.8, H 4.6, Br 12.0, Cl 10.2, N 7.7%.

Example 12

To a suspension of 0.49 g (16.3 m mol) 80% NaH oil dispersion in 15 ml abs. Dimethyl sulfoxide (DMSO) was added dropwise at room temperature to a solution of 1.023 g (14.83 m mol) of 1,2,4-triazole in 6 ml of abs. DMSO, stirred at RT for 30 min and then gave a solution of 6.85 g (10 m mol) of cis-2-bromomethyl-2- (2.4-dichlorophenyl) -4- [4- (4- (4- (4-methylpyrimidin-2-yl) benzyl) piperazin-1-yl) phenoxymethylJ-1,3-dioxolane in 7 ml Section. DMSO added dropwise and stirred for 20 hours at 130 ° C. under a nitrogen atmosphere. After cooling, the reaction mixture was stirred into 120 ml of water. This mixture was extracted several times with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ extracts were dried, filtered and in vacuo. evaporated. The residue (7.1 g) was purified by chromatography on a silica gel S-CH ₂ C1 ₂ column (0 2.6 cm, H 42 cm) as described in Example 6. From the fractions which were uniform according to TLC, 2.43 g (= ̂ 36.2% yield) became almost pure cis-2- (2.4-dichlorophenyl) -2- (1.2.4-triazol-1-ylmethyl) -4- [4 - (4- (4- (4-methyl-pyrimidin-2-yl) benzyl) piperazin-1-yl) phenoxymethyl] -1,3-dioxolane, mp 126-27 ° C, obtained; Analysis: C ₃₅ H ₃₅ Cl ₂ N ₇ O ₃ (672.64) calc. C 62.50, H 5.25, N 14.58; Found C 62.5 H 5.2 N 14.2%.

Example 13

• a) A mixture of 2.16 g (6 m mol) of 4- (4-hydroxyphenyl) -1- (4-methyl-2-phenyl-pyrimidin-5-ylmethyl) piperazine, 60 ml of toloule 2.22 g ( 6 m mol) of cis-2-bromomethyl-2- (4-fluorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolane, 0.40 g of tetrabutylammonium bromide and 8 ml of 50% sodium hydroxide solution were stirred intensively at 56 ° C. for 3.75 hours . The phases were then separated at room temperature, the sodium hydroxide solution was shaken three times with ether and toluene and ether phases were combined. These were shaken out three times with water, dried, filtered and evaporated in vacuo. The remaining residue (5.0 g) was on a silica gel S / CH ₂ C1 ₂ column (0 2.1 cm, H 30 cm) eluting with CH ₂ C1 ₂ and CH ₂ Cl ₂ / C ₂ OH mixtures (100: 0.25-100: 1 v / v) chromatographed. After elution of a pre-zone (0.45 g), the DC-uniform fractions were combined and i. Vac. evaporated. 3.40 g (= ̂ 89.5% yield) of cis-2-bromomethyl-2- (4-fluorophenyl) -4- [4- (4- (4-methyl-2-phenylpyrimidine-5- ylmethyl) -piperazin-1-yl) -phenoxymethylJ-1.3- dioxolane as a highly viscous oil ("cis" refers to the 2-bromomethyl group and the "4-hour" phenoxymethyl group); Analysis: C ₃₃ H ₃₄ BrFN ₄ O ₃ (MG 633.58) calc. C 62.56, H 5.41, Br 12.61, F 3.00, N 8.84; Found C 62.1, H 5.3, Br 15.0, F 2.9, N 8.8%.
• b) As described in Example 10b, 3.40 g (5.36 mol) of cis-2-bromomethyl-2- (4-fluorophenyl) -4- [4- (4- (4-methyl-2-phenyl- pyrimidin-5-ylmethyl) piperazin-1-yl) phenoxymethylJ-1,3-dioxolane with 0.714 g (10.5 m mol) imidazole and 0.315 g (10.5 m mol) 80% NaH oil dispersion in 33 ml abs. NN-dimethylacetamide implemented. After refluxing for 30 hours, the dimethylacetamide was distilled off in an oil pump vacuum on a rotary evaporator. The residue was taken up in CH ₂ Cl ₂ / water. After separation of the phases, the aqueous was extracted several times with CH ₂ C1 ₂ . The combined CH ₂ Cl ₂ extracts were shaken out with water, dried, filtered and i. Vac. evaporated. The residue (3.96 g) was chromatographed on a silica gel S / CH ₂ Cl ₂ column (Ø 2.1 cm, height 34 cm) eluting with CH ₂ Cl ₂ and CH ₂ Cl _{2 /} C ₂ H ₅ OH- Mixtures ₍ with increasing _C2H50H content, up to a maximum of 5 vol% C ₂ H ₅ 0H). After elution of 2.5 g of 2-bromomethyl-dioxolane starting compound, DC-uniform fractions were combined and i. Vac. evaporated. This gave the residue 0.51 g of almost pure cis-2- (4-fluorophenyl) -2- (imidazol-1-ylmethyl) -4- [4- (4- (4-methyl-2-phenyl-pyrimidine-5) -ylmethyl) -piperazin-1-yl) -phenoxymethylj-1,3-dioxolane (yield = ̂ 15.3%),

Analysis: C ₃₆ H ₃₇ FN ₆ O ₃ (MW 620.74) calc. C 69.66 H 6.01 F 3.06 N 13.54; Found C 68.6, H 6.0, F 2.9, N 13.2%.

Example 14

A mixture of 3.77 g (14 moles) of 4- (4-hydroxyphenyl) -1- (pyrid-2-ylmethyl) piperazine, 200 ml of toluene, 5.88 g (14 moles) of 2-bromomethyl-2 - (2.4-dichlorophenyl) -4-methanesulfonyloxymethyl-1,3-dioxolane, 0.80 g tetrabutylammonium bromide and 27 ml 50% sodium hydroxide solution was stirred intensively at 65 ° C. for 3 hours. The phases were then separated at room temperature. The toluene solution was shaken three times with water, dried, filtered and in vacuo. evaporated. The remaining residue (8.8 g) was on a silica gel S / CH ₂ C1 ₂ column (f 2.6 cm, H 28.0 cm) eluting with CH ₂ C1 ₂ and CH ₂ Cl _{2 /} C ₂ H ₅ OH mixtures (up to a maximum of 4 vol.% C ₂ H ₅ 0H content) chromatographed. After elution of a pre-zone (1.45 g), the DC-uniform fractions were combined and i. Vac. evaporated. This gave 6.02 g (= ̂ 72.4% yield) of 2-bromomethyl-2- (2.4-dichlorophenyl) -4- [4- (4- (pyrid-2-ylmethyl) piperazin-1-yl) - phenoxymethylJ-1,3-dioxolane (cis / trans mixture) as a highly viscous oil, analysis: C ₂₇ H ₂₈ BrCl ₂ N ₃ O ₃ (M ^G 593.3 ⁸ ) Ber.C 54.65, H 4.76, Br 13 , 47, Cl 11.95, N 7.08; Found C 53.5, H 4.9, Br 13.1, Cl 13.2, N 6.5%.

Example 15

As described in Example 10b, 4.75 g (8 moles) of 2-bromomethyl-2- (2,4-dichlorophenyl) -4- [4- (4- (pyrid-2-ylmethyl) piperazin-1-yl ) -phenoxymethyl] -1.3-dioxolane with 0.68 g (10 m mol) imidazole and 0.30 g (10 m mol) 80% NaH oil dispersion in 28 ml abs. NN-dimethylacetamide to give 1.53 g (= ̂ 33% of theory) of 2- (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4- [4- (4- (pyrid-2 -ylmethyl) -piperazin-1-yl) -phenoxymethylJ-1,3-dioxolane; Mp 134-35 ° C, analysis: found C 61.7 H 5.2 N 12.0% (calculated values see Example 6, No. 2.21) implemented.

Examples of the manufacturing process variant D) Example 16

A solution of 2.45 g (5 m mol) of 2-S, (R) - (2.4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4-R, (S) - (4-piperazinophenoxymethyl) - 1,3-dioxolane (cis form) and 1.87 g (5 m mol) of 2- (4-bromomethyl-1-phenyl) -4,6-dimethyl-pyrimidine in 20 ml abs. DMF was heated to 80 ° C. with protection against atmospheric moisture and, after 10 minutes, 115 mg of powdered potassium carbonate were added with stirring. After a further 25 minutes, a further 115 mg of powdered K ₂ CO ₃ and after a further 60 minutes a third portion of 115 mg of the same K ₂ CO ₃ (a total of 345 mg (2.5 moles) K ₂ CO ₃ ) were added. . The mixture was subsequently stirred at 80 ° C. for 3 hours, the DMF was distilled off in an oil pump vacuum on a rotary evaporator and the residue was taken up in 30 ml of water and 100 ml of CH ₂ Cl ₂ . After separation of the phases, the aqueous was extracted twice more with CH ₂ Cl ₂ . The combined CH ₂ Cl ₂ extracts were dried, filtered and i. Vac. evaporated. The residue (3.72 g) was purified by column chromatography on silica gel S / CH ₂ C1 ₂ as described in Example 6. 2.71 g (79% of theory) of pure cis-2- (2,4-dichlorophenyl) -2- (imidazol-1-ylmethyl) -4- [4- (4- (4- (4.6-dimethyl -pyrimidin-2-yl) -benzyl) -piperazin-1-yl) -phenoxymethyl] -1,3-dioxolane as a viscous oil; Analysis: Found C 64.6, H 5.5, N 12.0% (see Example 6, No. 2.17).

Example 17

Using the same procedure as described in Example 16, starting from IXa or IXb (cf. Table 4) and in each case the corresponding compound of the formula Xa, the compounds of the formula I listed in Table 4 were prepared by process variant D).

Example 18

In principle, the same procedure as described in Example 16, starting from 5 m mol of IXb and 5 m mol of 3-chloromethyl-pyridine hydrochloride, but in 25 ml abs. Dimethyl sulfoxide (DMSO), instead of DMF as solvent, and using an additional 2.5 moles of powdered potassium carbonate (thus a total of 5 moles of K ₂ CO ₃ ) were, after appropriate processing of the reaction mixture as described in Example 16, 1.80 g (62% of theory) cis-2- (2,4-dichlorophenyl) -2- (1.2.4-triazol-1-ylmethyl) -4- [4- (4- (pyrid-3-ylmethyl) piperazine -1-yl) phenoxymethyl] -1,3-dioxolane, m.p. 106-107 ° C, obtained; Analysis: Found C 59.6, H 5.0, N 14.3% (see Example 6, No. 2.23).

Examples of the preparation of compounds of formula IIIa Example 19

A mixture of 4.94 g (14.5 moles) of 1- (4-hydroxyphenyl) piperazine dihydrobromide, 3.29 g (14 moles) of 4-chloromethyl-6-methoxy-2-phenyl-pyrimidine and 2 , 00 g (14.5 m mol) of powdered potassium carbonate in 50 ml of abs. NN-dimethylformamide (DMF) was heated to 80 ° C. and 322 mg of pulverized K ₂ CO _{3 were added} with stirring after 10 minutes, after a further 25 minutes and after a further 60 minutes, with a nitrogen blanket (total addition of 966 mg (7 m mol) K ₂ CO ₃ ). The mixture was subsequently stirred at 80 ° C. for 2.5 hours, the DMF was largely distilled off in an oil pump vacuum on a rotary evaporator and the crystalline residue was mixed with 40 ml of water and 50 ml of CH ₂ C1 ₂ and adjusted to pH 5-6 with 2N HCl , separated the phases and extracted the aqueous three times with CH ₂ Cl ₂ . The combined CH ₂ C1 ₂ extracts were dried, filtered and evaporated in vacuo. The residue (4.25 g) was eluted on a silica gel S- ^CH 2C12 column (Ø 2.0, height 23 cm) CH ₂ Cl ₂ and CH ₂ Cl ₂ / C ₂ H ₅ OH mixtures, increasing C ₂ H ₅ OH content (up to a maximum of 4 vol% -C ₂ H ₅ OH) chromatographed. The DC-uniform fractions were combined and crystallized from CH ₃ 0H. This gave 3.06 g (= = 58% yield) of 4- (4-hydroxyphenyl) -1- (6-methoxy-2-phenyl-pyrimidin-4-ylmethyl) piperazine; Mp 166-67 ° C, analysis: ^C ₂₂ ^H ₂₄ N ₄ 0 ₂ (MW 376.46) calc. C 70.19, H 6.43, N 14.88; Found C 69.9, H 6.4, N 14.5%.

Example 20

A mixture of 4.46 g (25 m mol) of 1- (4-hydroxyphenyl) piperazine and 5.52 g (25 m mol) of 6-chloromethyl-2-phenyl-pyrimidone- (4) in 90 ml abs. NN-dimethylformamide (DMF) was heated to 80 ° C. and, with stirring after 10 min., After another 25 min. And after another 60 min., 576 mg of pulverized K ₂ CO _{3 were added} under a nitrogen atmosphere (total addition of 1 , 73 g (12.5 m mol) K ₂ C0 ₃ ) and 3.5 hours at 80 ° C stirred. The DMF was then largely distilled off in vacuo on a rotary evaporator, 170 ml of water and 17 ml of 4 nHCl were added to the residue, and the resulting mixture was extracted three times with CH ₂ C1 ₂ . The CH ₂ C1 ₂ extract was discarded. Activated carbon was added to the acidic aqueous solution, shaken and suction filtered. The filtrate was neutralized with 2 nNaOH. The resulting crystalline precipitate was filtered off, washed with water, boiled with methanol for 5 minutes and, after cooling to 10-15 ° C., suction filtered and dried. 6.25 g (= ̂ 69% yield) of pure 4- (4-hydroxyphenyl) -1- (2-phenyl-3,4-dihydro-pyrimidin-4-one-6-ylmethyl) piperazine hydrate, mp. 246-48 ° C, analysis: ^C ₂₁ ^H ₂₄ ^N ₄ ⁰ ₃ ^(MW 380.45) Ber.C 66.30 H 6.36 N 14.73; Found C 65.9 H 6.1 N 14.5%.

Example 21

Following the same procedure as described in Example 20, starting from 3.39 g (19 m mol) of 1- (4-hydroxyphenyl) piperazine and 4.20 g (17.9 m mol) of 6-chloromethyl-3,4-dihydro -3-methyl-2-phenyl-pyrimidin-4-one, using 1.24 g (9 m mol) of K ₂ CO ₃ , 4.42 g (= ̂ 65.6% yield) 4- (4- Hydroxyphenyl) -1- (3,4-dihydro-3-methyl-2-phenyl-pyrimidin-4-one-6-ylmethyl) piperazini mp 206-07 ° C, analysis; C ₂₂ H ₂₄ N ₄ O ₂ (MW 376.46) Calc. C 70.19, H 6.43, N 14.88; Found C 69.2, H 6.4, N 14.5%; receive. To work up the reaction mixture, the DMF i. Vac. evaporated, the residue was taken up in water / CH ₂ C1 ₂ and neutralized and the CH ₂ C1 ₂ extract residue was crystallized from CH ₃ 0H.

Example 22

A mixture of 2.59 g (14.5 mol) of 1- (4-hydroxyphenyl) piperazine and 3.90 g (14 mol) of 2- (4-bromomethyl-1-phenyl) -4.6-dimethyl-pyrimidine in 40 ml abs. DMF was mixed with 325 mg (in total 975 mg (7 m mol)) of pulverized K ₂ CO ₃ at 80 ° C. with stirring after 10 minutes, after a further 30 minutes and after a further 60 minutes, and then for a further 3 hours. stirred at 80 °. After evaporating the DMF in vacuo, the crystalline residue was taken up in about 50 ml of water, the mixture was neutralized, shaken for 20 minutes and then suction filtered. The filter residue was washed out with water and then refluxed with 30 ml of CH ₃ 0H for 5 minutes. The cooled mixture was suctioned off and the solid was dried. This gave 3.15 g (= ̂ 59.7% yield) of 4- (4-hydroxyphenyl) -1- (4- (4.6-dimethylpyrimidin-2-yl) benzyl) piperazine, mp 165-67 ° C,

Analysis: C23H26N40 (MW 374.49) Calc. C 73.77 H 7.00 N 14.96; Found C 73.6, H 7.0, N 14.7%.

Example 23

According to the working method described in Examples 19-22, starting from a compound of the formula XIVa and in each case the corresponding bromine or chloromethyl compound of the formula X (E "= Br or Cl; Y see Table 5), the values in the table 5 listed compounds of formula IIIa prepared.

If the residue which remained after the DMF had been distilled off gave a crystalline product when taken up in water and neutralized, this was worked up further as described in Example 22. If no crystalline substance was obtained at this point, the mixture was extracted with CH ₂ C1 ₂ . The CH ₂ C1 ₂ extract residue was crystallized from CH ₃ 0H or CH ₃ CN. If no crystalline substance was obtained in this way or the resulting substance was too contaminated, the CH ₂ C1 ₂ extract residue was removed on a silica gel S / CH2C12 column by elution with CH ₂ C1 ₂ and CH ₂ Cl ₂ / C ₂ H ₅ OH mixtures purified by chromatography. Compounds of the formula IIIa which are contained in Table 5 and are chromatographically purified are marked with " ^* ".

Example 24

To a mixture of 1.78 g (10 moles) of 1- (4-hydroxyphenyl) piperazine, 3.05 g of 95% 5-bromomethyl-4-methyl-2-phenyl-pyrimidine (= ̂ 11 moles) and 80 ml abs. 1,2-dimethoxyethane was stirred with 30 minutes at 45 ° C a solution of 1.05 g triethylamine in 20 ml abs. Dimethoxyethane added dropwise. The mixture was stirred for 1 hour at 45 ° C. and 3 hours at 80 ° C., the solvent was evaporated in vacuo, the residue was taken up in CH ₂ C1 _{2 /} water, neutralized to pH 6-7, the phases were separated and the was extracted aqueous phase three times with CH ₂ Cl ₂ . The combined CH ₂ C1 ₂ extracts were dried, filtered and i. Vac. evaporated. The crystalline residue (3.7 g) was recrystallized from methanol.

2.35 g (65% of theory) of pure 4- (4-hydroxyphenyl) -1- (4-methyl-2-phenyl-pyrimidin-5-ylmethyl) piperazine, mp. 201-202 ° C., were obtained .

This synthesis can also be carried out with 1- (4-hydroxyphenyl) piperazine dihydrobromide. In this case, 3.10 g (30.7 m mol) of trietylamine are used in a 10 m mol batch and the reaction time at 45 ° C. is extended to 12 hours and that at 80 ° C. to 6 hours. About the same amount of pure 4- (4-hydroxyphenyl) -1- (4-methyl-2-phenyl-pyrimidin-5-ylmethyl) piperazine is obtained as in the above embodiment with the base of the piperazine derivative.

Examples for the preparation of bromomethyl-pyrimidines starting materials for the synthesis of compounds of the formula IIIa: Example 25

A solution of 5.53 g (30 moles) of 4,5-dimethyl-2-phenylpyrimidine in 110 ml of CCl ₄ was mixed with 5.54 g (31.1 moles) of N- Bromosuccinimide (NBS) and 6 mg of dibenzoyl peroxide were added and heated to boiling temperature for 5 minutes with stirring and irradiation with a daylight lamp with an increased short-wave content (type: Osram Ultra-Vitalux, 300 W, GUR 53). After that, the NBS was consumed and changed to specifically light succinimide. At room temperature, this was suctioned off and washed with a little CC14. The filtrate was i. Vac. evaporated, the residue dissolved in 100 ml of diisopropyl ether, the solution clarified over diatomaceous earth and the clear filtrate again i. Vac. evaporated. This gave 7.70 g, according to the ¹ H-NMR spectrum 94.5%, 5-bromomethyl-4-methyl-2-phenyl-pyrimidine, (= ̂ 92% yield), mp. 65-66 ° C, analysis : C ₁₂ H1 _1B rN ₂ (MG 263.15) calc. C 54.77 H 4.21 Br 30.37 N 10.65; Found C 53.5, H 3.9, Br 31.3, N 10.0%.

Example 26

A solution of 5.12 g (21.2 m mol) of 3,4-dihydro-3,5-dimethyl-2-phenyl-6-propyl-pyrimidin-4-one in 80 ml of CCl ₄ was treated with 4.19 g (23.5 m mol) of NBS and 5 mg of dibenzoyl peroxide are added and the mixture is heated to boiling temperature for 7 minutes with stirring and irradiation (cf. Example 25). The NBS then changed to succinimide. It was suctioned off, washed with CC1 ₄ and the filtrate i. Vac. a. The residue was dissolved in n-pentane / diisopropyl ether 2: 1, the cloudy solution was clarified with diatomaceous earth and the clear filtrate i. Vac. again evaporated to constant weight. According to the ¹ H-NMR spectrum, the residue (7.1 g) consisted of 65% 5-bromomethyl-3,4-dihydro-3-methyl-2-phenyl-6-propyl-pyrimidin-4-one (or the corresponding 1.4 -Dihydro-1-methyl compound; cf.pyrimidones mentioned for Y under b ₂ ). In this form, this bromomethyl compound was reacted with 1- (4-hydroxyphenyl) piperazine to form the compound of the formula IIIa described in Example 23, Table 5, No. 5.24.

Example 27

A solution of 4.50 g (22.7 moles) of 2-ethyl-4- (4-tolyl) pyrimidine in 90 ml of CC1 ₄ was added with 4.04 g (22.7 moles) of NBS and 3 mg of dibenzoyl peroxide added and heated to boiling temperature for 3 min with stirring and irradiation (cf. Example 25). The NBS then changed to succinimide. After cooling to room temperature, the product was washed with CC1 ₄ and the filtrate was evaporated i. Vac. a. The residue was dissolved in diisopropyl ether, the cloudy solution was clarified with diatomaceous earth and the clear filtrate i. Vac. again evaporated to constant weight. According to the ¹ H-NMR spectrum, the residue (5.83 g) consisted of approximately 43% of [4- (4-bromomethyl-phenyl) -2-ethyl-pyrimidine and approximately 34% of 2- (1- Bromoethyl) -4- (4-tolyl) pyrimidine and approximately 23% from unchanged 2-ethyl-4- (4-tolyl) pyrimidine. This mixture was reacted with 1- (4-hydroxyphenyl) piperazine to form the corresponding 4- (4-hydroxyphenyl) piperazine derivatives. The two structurally isomeric piperazine derivatives were separated by chromatography on a silica gel S-CH ₂ C1 ₂ column and the compound of the formula IIIa described in Example 23, Table 5, No. 5.6 was obtained in pure form.

Example 28

A solution of 2.73 g (12.5 moles) of 4- (4-chlorophenyl) -2.5-dimethyl-pyrimidine in 48 ml of CC1 ₄ was made up with 2.26 g (12.7 moles) of NBS and 3 mg of dibenzoyl peroxide were added and the mixture was refluxed for 5 minutes with stirring and irradiation (cf. Example 25). The NBS then changed to succinimide. At room temperature, the mixture was filtered off with suction, washed with CCl ₄ and the filtrate was evaporated in vacuo. The residue was dissolved in about 60 ml of diisopropyl ether / n-pentane 1: 1, the slightly cloudy solution was clarified with diatomaceous earth, again suctioned off and the clear filtrate was evaporated to constant weight in an oil pump vacuum. The residue (3.4 g) consisted of 69.5% 5-bromomethyl-4- (4-chlorophenyl) -2-methyl-pyrimidine (= ̂ 63.5% yield) according to the ¹ H-NMR spectrum. In this form, this bromomethyl compound was used for the reaction with 1- (4-hydroxyphenyl) piperazine (cf. Example 23, No. 5.19).

Example 29

Following the procedure described in Example 28, starting from 2.37 g (14 m mol) of 2- (4-tolyl) pyridine in 80 ml CC1 ₄ , 2.60 g (14.6 m mol) NBS and 3 mg dibenzoyl peroxide obtained as a crystalline evaporation residue of 3.61 g, according to the ¹ H-NMR spectrum about 82% 2- (4-bromomethylphenyl) pyridine, mp. 51-52 ° C (yield = ̂ 85% of theory ).

In this form, the bromomethyl compound was reacted with 1- (4-hydroxyphenyl) piperazine to form the compound of the formula IIIa described in Example 23, No. 5.31.

As an example of the high local in vivo activity of the compounds according to the invention, treatment results are given in laboratory animals experimentally infected with Trichophyton mentagrophytes.

To determine the local effectiveness, two 450-500 g guinea pigs (Pirbright white strain) were infected with 1.5 x 10 ⁴ conidia / animal in the epidermis, distributed over 6 infection points.

The animals were treated dermally from the 3rd day after the infection on 5 consecutive days by applying a 0.1% preparation solution on 3 infection sites on the back. The other back was treated in the same way with vehicle without preparation. In addition to the animals treated with the substances according to the invention, two animals were treated with the reference substance terconazole, two animals remained untreated after the infection.

Als Beispiel für die hohe orale und parenterale in-vivo-Wirksamkeit der erfindungsgemäßen Verbindungen werden Behandlungsergebnisse an experimentell mit Candida albicans infizierten Labortieren angeführt.As can be seen in Table 6, the compounds according to the invention showed a significantly greater reduction in the mycosis diameter than the standard preparation terconazole, ie the antifungal effect of the compound according to the invention was up to 60% superior to that of terconazole.

As an example of the high oral and parenteral in vivo activity of the compounds according to the invention, treatment results are given in laboratory animals experimentally infected with Candida albicans.

To determine the oral and parenteral activity, groups of 5 18-20 g mice each (strain HOE: NMRKF; SPF 71) were given 2. 10 ^S germs / animal infected.

The animals were treated orally or subcutaneously in 8 equal single doses of 30 mg / kg or 10 mg / kg body weight (-24 / -18 / -2h / + 2/24/30/48 / 54h).

In addition to the group of 5 animals treated with substances I according to the invention, a group of likewise 5 animals was treated with the reference substance ketoconazole for comparison. A control group of 10 animals remained untreated after infection.

As can be seen from Table 7, the survival time of the animals after the infection was increased by up to twice with the compounds according to the invention, compared with the current standard preparation ketoconazole.

Claims (14)

1. Process for the preparation of compounds I

in the A CH or N, Ar denotes naphthyl, thienyl, halothienyl or an unsubstituted or a phenyl group which has up to 3 substituents, where the substituents can be identical or different and F, Cl, Br, J, CF ₃ , OCH ₃ , OC ₂ H ₅ , CH ₃ , C ₂ H ₅ or phenoxy, R ¹ C ₁ -C ₃ alkyl, F or Cl, g 0, 1 or 2 and Y the following heterocyclic radicals

in which R ² H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be identical or different and F, Cl, Br, J, CF ₃ , OCH ₃ , OC ₂ H ₅ , N0 ₂ or C ₁ -C ₄ alkyl, or an unsubstituted or a phenyl C ₁ -C ₂ alkyl group carrying 1 or 2 substituents in the phenyl radical, it being possible for the substituents to be the same or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , or in the case of the residue a ₁ additionally C ₁ -C ₄ alkthio, an unsubstituted or a benzylthio group carrying 1 or 2 substituents in the phenyl residue , where the substituents can be identical or different and mean F, Cl, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , and R ³ H, OH, Cl, C ₁ -C ₄ alkoxy or an unsubstituted or a benzyloxy group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ and in the heterocyclic radical a ₁ additionally C ₁ -C ₄ -alkyl or an unsubstituted or with an F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ substituted phenyl group and in the heterocyclic radical b ₁ additionally C ₁ -C ₄ alkyl or an unsubstituted or a 1 or 2 substituent-bearing phenyloxy group, where the substituents can be the same or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , R ⁴ H, Cl, Br, C ₁ -C ₄ alkyl or CN, R ⁵ H, C ₁ -C ₄ -alkyl, prop-2-en-1-yl, prop-2-in-1-yl or benzyl, p denotes 0 or 1, the phenylene radical being bonded via the 2,3 or 4-position in a ₁ , a ₂ and c, and R ⁶ H, C ₁ -C ₈ alkyl, (C ₃ -C ₆ cycloalkyl) -C ₁ -C ₃ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be identical or different and F , Cl, Br, J, OCH ₃ , OC ₂ H ₅ , 1,2-O-CH ₂ -O-, CF ₃ or C ₁ -C ₄ alkyl, an unsubstituted or in the phenyl radical by OCH ₃ , OC ₂ H ₅ , 1,2--0-CH ₂ -0-, CF ₃ , ^F, Cl or C ₁ -C ₄ alkyl-substituted phenyl-C ₁ -C ₂ alkyl group, or CF ₃ , and R ⁷ and R ⁸ independently of one another are H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or an unsubstituted or a phenyl or benzyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ or OC ₂ H ₅ , and where R ^{7 can} also mean OH, and _R ⁹ denotes H, Cl, Br or CN, or

or

in which p 0 or 1, R ^{10 is} Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , n is 0, 1 or 2, where R ¹⁰ in d _{1 is} in 3, 4, 5 and / or 6 , in d _{2 can be} in 2-, 4-, 5- and / or 6- and in d ₃ in 2-, 3-, 5- and / or 6-position, and R ¹¹ denotes Cl, OCH ₃ , CH ₃ or C ₂ H ₅ and in d ₄ and d ⁵ 'can be in one or two of the free positions, and the heterocyclic radical d _{4 can be} via the 2-, 3- or 4- Position and the heterocyclic radical d ₅ is bonded via the 5-, 6-, 7- or 8-position and the phenylene unit in the radical d ₁ is bonded via the 2,3 or 4- (para) position,
as well as their physiologically tolerable acid addition salts, characterized in that A) a compound of formula II

in the A and Ar have the meanings given for formula I and E denotes halogen, acyloxy, C ₁ -C ₃ -alkylsulfonyloxy, or arylsulfonyloxy,
with a compound of formula III

in the MH, an alkali or alkaline earth metal means and R ¹ , g and Y have the meanings given for formula I, or that B) a compound of the formula IV,

in the Ar have the meanings given for formula I and E and E 'for E in formula II, first reacted with a compound of the formula III and in doing so produces a compound of the formula V

in the Ar, R, g and Y have the meanings given for formula I and E 'for formula II for E, and then reacting a compound of formula V with a compound of formula VI,

in the A, CH or N and _M 'denotes H, an alkali or alkaline earth metal or Si (CH ₃ ) ₃ , or that one C) a compound of formula VII,

in which A and Ar have the meanings given for formula I, with a 1,2-diol of the formula VIII,

in which R ¹ , g and Y have the meanings given for formula I,
or that one D) a compound of formula IX,

in which A, Ar, R ¹ and g have the meanings given for formula I, with a compound of formula X,

in which E "denotes Cl, Br, J, acyloxy, alkylsulfonyloxy or arylsulfonyloxy and Y denotes the formula I under a ₁ , a ₂ , b ₁ , b ₂ , c, d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and d ₇ has the meanings given, and, if appropriate, the compounds of the formula I obtained according to route A) -D) are converted into their physiologically tolerated acid addition salts using inorganic or organic acids. 2. A method for producing a compound I according to claim 1, characterized in that at least one of the substituents or indices has the following meaning: A CH or N, Ar is a phenyl group substituted by 1 or 2 F or Cl atoms, R ¹ CH ₃ or C ₂ H ₅ , g 0 or 2, Y to the heterocyclic radicals a ₁ , a ₂ , b ₁ , b ₂ and c: R ² H, C ₁ -C ₄ alkyl, CH ₃ 0 or an unsubstituted or a phenyl radical carrying 1 or 2 substituents or a benzyl group , where the substituents can be identical or different and denote F, Cl, Br or OCH ₃ , R ³ H or C ₁ -C ₄ alkoxy and in the heterocyclic radical a ₁ additionally CH ₃ or an unsubstituted or a phenyl group substituted by an F, Cl, OCH ₃ or CH ₃ and in the radical b ₁ additionally an unsubstituted or a 1 or Phenyloxy group carrying 2 substituents, where the substituents can be identical or different and denote F, Cl, Br, OCH3 or OC ₂ H ₅ , R is H or CN, and when a heterocyclic group ₁ ^to-sows zlich C ₁ -C ₄ alkyl, R ⁵ CH ₃ , p 0 or 1, R ⁶ H, C ₁ -C ₈ alkyl, (C ₅ -C ₆ cycloalkyl) -C ₁ -C ₂ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F , Cl, Br, OCH ₃ , OC ₂ H ₅ or CF ₃ , an unsubstituted or substituted in the phenyl radical by OCH ₃ , CF ₃ , F or Cl or CF ₃ , R ⁷ , R ⁸ independently of one another are C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or a phenyl or phenyl group substituted by F, Cl, OCH ₃ or OC ₂ H ₅ and R ⁷ above also H or OH, R ⁹ H or CN, for the heterocyclic radicals d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and ^d 7 ^: p 0 or 1, _R ¹⁰ Cl, CH ₃ or ^C ₂ ^H ₅ n is 0 or 1, where R ¹⁰ in d _{3 is} preferably in the 2 position, and R ¹¹ Cl, the phenylene unit in the rest d ₁ preferably being bonded via the 4-position. . Process for producing a compound I according to claim 1, characterized in that at least one of the substituents or indices has the following meaning: A CH or N, Ar 2,4-dichlorophenyl, R ¹ CH ₃ , g 0 or 2, ^Y
to the heterocyclic radicals a ₁ , a ₂ , b ₁ , b ₂ and c: R ² CH ₃ or an unsubstituted or a phenyl or 1 or 2 substituent phenyl or a benzyl group, where the substituents may be the same or different and F or Cl and in the phenyl group and in the a _{1 group} in the phenyl and benzyl group additionally mean OCH ₃ , and in the remainder a ₁ additionally C ₂ -C ₄ alkyl, ^R3 in the a ₁ radical, if p = 0, CH ₃ or an unsubstituted or substituted by an F, Cl or OCH ₃ phenyl group, and, if p = 1, H, in the b radical ₁ H or one by OC ₂ H ₅ substituted phenyloxy group, R ⁴ H or in the case of the rest a ₁ , if p = 0, additionally CH ₃ R ⁵ CH ₃ p for the heterocyclic radicals a ₁ and a ₂ 0 or 1 and for the heterocyclic radical c 1 R ⁶ H, CH ₃ or an unsubstituted or simply substituted by F, Cl, OCH ₃ or OC ₂ H ₅ , R ⁷ , R ₈ independently of one another are CH ₃ or an unsubstituted or a phenyl group which is substituted by F, Cl or OCH ₃ and R ⁷ moreover also H or C ₁ -C ₄ alkoxy, _R ⁹ H
the remainder d4 preferably being bound via the 2-position and the remainder d5 preferably via the 6- or 7-position. 4. Process for the preparation of compounds of formula IIIa

in which mean: R ^{1 is} C ₁ -C ₃ alkyl, F or Cl, g 0, 1 or 2 and Y the following heterocyclic radicals

in which _R ² H, C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F, Cl, Br, J, trifluoromethyl, methoxy , Ethoxy, nitro or C ₁ -C ₄ alkyl, or an unsubstituted or a phenyl C ₁ -C ₂ alkyl group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br , OCH ₃ , O ^C ₂ ^H ₅ , CH ₃ or C ₂ H ₅ , or, in the case of the heterocyclic radicals a ₁ and a ₂ , if p is zero, furthermore also C ₁ -C ₄ -alkylthio or an unsubstituted or an im Phenyl radical 1 or 2 substituent-bearing benzylthio group, the substituents being the same or can be different and are F, Cl, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , means and R ³ H, OH, Cl, C ₁ -C ₄ alkoxy or an unsubstituted or a benzyloxy group bearing 1 or 2 substituents in the phenyl radical, where the substituents can be identical or different and F, Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or ^C ₂ ^H ₅ , and in the heterocyclic radical a ₁ additionally C ₁ -C ₄ alkyl or an unsubstituted or with an F, Cl, Br, OCH3, OC ₂ H ₅ , CH ₃ or C ₂ H ₅ substituted phenyl group and, in the heterocyclic radical b1, additionally C ₁ -C ₄ alkyl or an unsubstituted or a 1 or 2 substituent phenyloxy group, where the substituents can be the same or different and F, Cl, Br, OCH3, OC ₂ H ₅ , ^{Represent CH} ₃ or C ₂ H ₅ , R ⁴ H, Cl, Br or CN or C ₁ -C ₄ alkyl R ⁵ H, C ₁ -C ₄ alkyl, prop-2-en-1-yl, prop-2-in-1-yl or benzyl p denotes 0 or 1, where in a ₁ , a ₂ and c the phenylene radical is bonded via the 2,3 or 4 position and R ⁶ H, C ₁ -C ₈ alkyl, (C ₃ -C ₆ cycloalkyl) -C ₁ -C ₃ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be identical or different and F , Cl, Br, J, OCH ₃ , OC ₂ H ₅ , 1.2--0-CH2-0-, CF ₃ or C ₁ -C ₄ alkyl mean an unsubstituted or in the phenyl radical by OCH ₃ , OC ₂ H ₅ , 1.2--0-CH ₂ -0-, ^CF ₃ , F, Cl or C ₁ -C ₄ alkyl-substituted phenyl-C ₁ -C ₂ alkyl group, or CF ₃ , and R ⁷ and R ⁸ are independently H, C ₁ -C ₈ alkyl, C ₁ - ^C ₄ alkoxy, or an unsubstituted or bearing 1 or 2 substituents in the phenyl phenyl or benzyl, wherein the substituents may be identical or different and F, Cl, Br, OCH ₃ or OC ₂ H ₅ , and where _R ^{7 can} also mean OH, and _R ⁹ denotes H, Cl, Br or CN, or

or

or

in which p 0 or 1, R ¹⁰ Cl, Br, OCH ₃ , OC ₂ H ₅ , CH ₃ or C ₂ H ₅ , n denotes 0, 1 or 2, where R ¹⁰ in d ₁ in 3,4,5 and / or 6-, in d ₂ in 2,4,5 and / or 6- and in d ₃ in 2,3,5 -and / or 6-position, and R ^{11 is} Cl, OCH ₃ , CH ₃ or C ₂ H ₅ and is in d ₄ and d ₅ in one or two of the free positions, and the heterocyclic radical d ₄ via the 2,3 or 4-position and the heterocyclic Residue d _{5 is} bonded via the 5,6,7 or 8 position and the phenylene unit in residue d ₁ is bonded via the 2,3 or 4- (para) position, means
and of their acid addition salts, characterized in that a compound of formula XIV

in which R ¹ and g have the meanings given for formula I, or a salt of this compound, with a verb formula X,

in which E "denotes Cl, Br, J, acyloxy, alkylsulfonyloxy or arylsulfonyloxy and Y has the meanings given for the formula I under a ₁ , a ₂ , b ₁ , b ₂ , c, d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , d ₆ and d ₇ ,
reacted and, if appropriate, the compounds of the formula IIIa obtained are converted to their acid addition salts with inorganic or organic acids. 5. The method according to claim 4, characterized in that either for the reaction with compounds of formula XIV a) a compound of the formula Xa ₁ or of the formula Xa ₂ ,

in which R ² -R ^{5 have} the meanings given for formula I and E "is Cl or Br, or b) a compound of the formula Xb ₁ or of the formula Xb ₂ ,

in which R ² , R ³ , R ⁵ and R ^{6 have} the meanings given for formula I and E "Br", or c) a compound of the formula Xc,

in which R ⁷ , R ⁸ , R ⁹ and p have the meanings given for formula I and E "is Cl or Br, or d) a compound of the formula Xd ₁ , the formula Xd ₂ , the formula Xd ₃ , the formula Xd ₄ , the formula Xd ₅ , the formula Xd ₆ or the formula Xd ₇

in which R ¹⁰ , R ¹¹ , p and n have the meanings given for formula I and E "Cl or Br is used. 6. A process for the preparation of a compound A compound of formula _III a according to claim 4, characterized in that at least one of the substituents or indices R ¹ g, _Y , R ² -R ¹¹ , p and _{n has} the following meanings: R ¹ CH ₃ or C ₂ H ₅ g 0 or 2 Y
to the heterocyclic radicals a ₁ , a ₂ , b ₁ , b ₂ and c: R ² H, C ₁ -C ₄ alkyl, CH ₃ 0 or an unsubstituted or a phenyl group carrying 1 or 2 substituents or a phenyl or a benzyl group, where the substituents can be the same or different and _R ^{3 is} H or C ₁ -C ₄ alkoxy and, in the case of the a _1, additionally CH ₃ or an unsubstituted or a phenyl group which is substituted by an F, Cl, OCH ₃ or CH ₃ and, in the case of the b _{1 group,} additionally an unsubstituted or a 1 or 2 Phenyloxy group carrying substituents, where the substituents can be identical or different and denote F, Cl, Br, OCH ₃ or OC ₂ H ₅ , _R ⁴ H or CN, _R ⁵ C ^H ₃ , p 0 or 1 R ⁶ H, C ₁ -C ₈ alkyl, (C ₅ -C ₆ cycloalkyl) -C ₁ -C ₂ alkyl, an unsubstituted or 1 or 2 substituent-bearing phenyl group, where the substituents can be the same or different and F , Cl, Br, OCH ₃ , OC ₂ H ₅ or CF ₃ , an unsubstituted or substituted in the phenyl radical by OCH ₃ , CF ₃ , F or Cl or CF ₃ , _R ⁷ , _R ⁸ independently of one another are C ₁ -C ₈ alkyl, C ₁ -C ₄ alkoxy or an unsubstituted or a phenyl or benzyl group substituted by F, Cl, OCH ₃ or OC ₂ H ₅ and R ⁷ also H or OH, R ⁹ H or CN,
for the heterocyclic radicals d ₁ , d ₂ , d ₃ , d ₄ , d ₅ , _d6 and ^d ₇ ^: p 0 or 1, R ¹⁰ Cl, CH ₃ or C ₂ H ₅ , n is 0 or 1, where R ¹⁰ in d3 is preferably in the 2 position, and R ¹¹ Cl, the phenylene unit in the rest d ₁ preferably being bonded via the 4-position. 7. A process for the preparation of a pharmaceutical preparation, characterized in that a compound of the formula (I) according to Claim 1 or one of its salts, optionally together with a customary pharmaceutical carrier and / or bilayer, is brought into a dosage form suitable for pharmaceutical purposes. 8. Use of a compound I according to claim 1 as an antifungal. 9. Use of a compound of formula I according to claim 1 for the preparation of an antifungal medicament. 10th Process for the treatment of mycoses, characterized in that an effective amount of a compound I according to claim 1 is applied together with pharmaceutically suitable carriers.